- Email: [email protected]
Clinical pharmacokinetics and interaction of centchroman — A mini review
Contraception 81 (2010) 275 – 280
Review article
Clinical pharmacokinetics and interaction of centchroman — A mini review☆ Jawahar Lal⁎
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow 226001, India Received 12 February 2009; revised 12 November 2009; accepted 19 November 2009
Abstract This article provides a brief review of the information available regarding the published pharmacokinetics data for the nonsteroidal, oncea-week oral contraceptive, centchroman (INN: ormeloxifene). This agent is a unique need-oriented contraceptive agent which is included in the National Family Welfare Programme of India. Since 1991, centchroman has been used as a need-oriented contraceptive and is being given for treating dysfunctional bleeding of the uterus. Information regarding absorption, tissue distribution, elimination and kinetic interactions is discussed. © 2010 Elsevier Inc. All rights reserved. Keywords: Centchroman; Ormeloxifene; Selective estrogen receptor modulator; Pharmacokinetics; Drug–drug interaction
1. Introduction DL-Centchroman (INN: ormeloxifene; trans-7-methoxy2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidinoethoxy) phenyl] chroman hydrochloride) is a nonsteroidal selective estrogen receptor modulator and once-a-week oral contraceptive agent developed by the Indian Central Drug Research Institute (Lucknow, India) [1–17]. This agent's contraceptive activity is well established in rodents and primates, wherein a single oral dose of centchroman within 24 h of coitus successfully prevents pregnancy in rats, dogs and rhesus monkeys, and wherein the antifertility effect of centchroman is promptly reversible [5,18,19]. Centchroman inhibits implantation via inhibition of endometrial receptivity to blastocyst signals by antagonism of the action of nidatory estrogen, without altering the concentration or secretion pattern of nidatory estrogen and progesterone, hypothalamo-pituitary-ovarian axis, follicle maturation, ovulation, mating behavior, gamete transport or fertilization, and preimplantation development of embryos [20–30]. Clinically, centchroman has been reported to provide good pregnancy protection in women in postcoital as well as ☆
There was no funding provided for this study. ⁎ Tel.: +91 522 2612411 18x4406; fax: +91 522 2623938/2623405. E-mail addresses: [email protected], [email protected].
0010-7824/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2009.11.007
weekly regimens [6,9] and is marketed in India as a contraceptive pill [5]. Centchroman was introduced in Delhi in July 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex, Ltd., Thiruvananthapuram, India) and Centron (Torrent Pharmaceuticals India, Ltd., Ahmedabad, India) and included in the National Family Welfare Programme in 1995 [3,4,31,32]. Centchroman is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration than oral contraceptives [3–6,8–17]. Centchroman is effective for contraception in a 30- and 60-mg once-a-week postcoital dose regimen [5]. This regimen (30 mg once a week) suffered from some early failures (pregnancies, most of which happened during the initial period of its use) possibly due to inadequate circulating levels before attaining a steady state. To reduce the failure rates, centchroman is, at present, recommended to be used with an initial twice-a-week 30-mg dose for 12 weeks followed by a 30-mg once-a-week regimen [5,23,24]. Centchroman with the trade name of Sevista is nowadays being manufactured by Torrent Pharmaceuticals India for treating dysfunctional bleeding of the uterus. Due to its potent anti-estrogenic and weak estrogenic activities [5,6,9,19,22,26–30], it is also effective against advanced breast cancer [33] and may be therapeutically effective for
276
J. Lal / Contraception 81 (2010) 275–280
other clinical conditions such as dermatitis [34], osteoporosis [35], restenosis, endometriosis and uterine fibroids [36]. Centchroman as a racemate has been found to be a potent cholesterol-lowering pharmaceutical resulting in a significant decrease in serum concentrations [36]. Due to the widespread and long-term clinical use of this drug in humans, knowledge of centchroman pharmacokinetic behavior becomes essential. Nevertheless, little is known about the pharmacokinetics and interactions of centchroman in humans compared to animals. Thus, in this article, the literature is reviewed concerning the absorption, distribution, metabolism and excretion of centchroman in human, as well as the interactions of the drug. 2. Pharmacological properties In humans, centchroman behaves as a potent antiestrogen but also has weak estrogenic and antiprogestational actions [37,38]. Roy et al. [39] reported that centchroman can induce ovulation when given chronically in daily doses of 15, 30 or 60 mg for 10 to 20 days to women who are not ovulating. On weekly single-dose (30–60 mg) administration to healthy, ovulating women for contraception, centchroman does not alter basal or peak gonadotropin (FSH/LH) secretion or production of estradiol and progesterone. In addition, it does not block ovulation. At this dosage and frequency of administration, the reproductive endocrine effects of the drug remain to slightly increase the transport of the zygote through the oviducts, accelerate blastocyst formation and suppress uterine endometrial proliferation and decidualization. Apparently, the combined effect of these actions is capable of creating sufficient asynchrony between the developing zygote and endometrial maturation to prevent implantation [40]. Centchroman inhibits implantation via inhibition of endometrial receptivity to blastocyst signals by antagonism of action of nidatory estrogen, without altering the concentration or secretion pattern of nidatory estrogen and progesterone, hypothalamo-pituitary-ovarian axis, follicle maturation, ovulation, mating behavior, gamete transport or fertilization, and preimplantation development of embryos [20–30]. Centchroman manifests its contraceptive activity primarily by producing asynchrony between ovum transport and uterine preparation for its reception and does not affect the hypothalamic-pituitary-ovarian axis or the embryo. The antifertility effect is readily reversible and subsequent pregnancy is normal. Centchroman suppresses the receptors in the reproductive organs like the ovaries, uterus and breasts. But it stimulates the estrogen receptors of other organs like the bones. So, while it acts as a birth control pill [5], it may prevent breast cancer [33] and may be therapeutically effective for other clinical conditions such as osteoporosis [41], dermatitis [42], restenosis, endometriosis and uterine fibroids [43]. Centchroman inhibits osteoclast degradation by 30%, calmodulin-dependent cyclic nucleotide phosphodiesterase and the effects are calcium dependent [44]. Centchro-
man, in addition to its competitive antagonism at the estrogen receptor level, promotes the conversion of intracellular estradiol (E2) to estrone (E1), a biologically less active form, by activating 17-β-hydroxysteroid dehydrogenase II, thus decreasing the estrogen receptor pool. Moreover, centchroman causes indirect anti-progestational effects in the uterus by virtue of its anti-estrogenic profile rather than by blocking the progesterone receptors [45]. 3. Analytical methodology Centchroman has been quantitated in serum by liquid chromatography with fluorescence detection set at an excitation and emission wavelength of 280 and 310 nm, respectively [46]. The technique uses 1–2 mL of serum and exhibited a lower limit of quantitation (LOQ) of 2 ng/mL. In addition to plasma levels, Lal et al. [47] have validated a method for the unlabelled parent drug and its metabolite (centchroman and its 7-desmethylated metabolite) in serum and milk using 0.5 mL of the biomatrices and fluorescence detection with a LOQ of 1 and 2.5 ng/mL, respectively. Briefly, serum (0.5 mL) was basified with potassium hydroxide solution (25 μL, 1 M) and then extracted twice with diethyl ether. The combined organic layer was evaporated to dryness under vacuum, and the dried residue was reconstituted in 0.1 mL of mobile phase and analyzed by HPLC equipped with a Spheri 5-μm Cyano column preceded with a guard column. The detection was performed using a fluorescence detector set at excitation (280 nm) and emission (310 nm) wavelengths. Unknown concentrations of centchroman and one of its major metabolites were interpolated from the respective serum standard curves drawn. Milk samples were subjected to protein precipitation with acetonitrile, and the supernatant was evaporated to dryness before being extracted with diethyl ether. The dried extract was reconstituted in 0.1 mL mobile phase and analyzed by HPLC using fluorescence detection. In addition, Khurana et al. [48] developed a method for determination of centchroman and 7desmethyl centchroman in the human uterus using HPLC and fluorescence detection with a LOQ of 10 ng/g. Briefly, an endometrium sample (0.1 g) was minced with scissors and homogenized in 0.75 mL of phosphate buffer (10 mmol/L, pH 3) and rehomogenised upon addition of 1.75 mL acetonitrile. After evaporation of the supernatant (2 mL), the residue was dissolved in 0.2 mL potassium hydroxide (0.2 mol/L) and extracted twice with 2 mL of extraction solvent (60% n-hexane in ethyl acetate). The combined organic layer was evaporated to dryness and the dried extract was reconstituted in 0.1 mL mobile phase and analyzed by HPLC using fluorescence detection. 4. Pharmacokinetics The pharmacokinetic properties of centchroman have been investigated in healthy female volunteers and nursing
J. Lal / Contraception 81 (2010) 275–280
277
mothers. The studies have used a liquid chromatographic method. Oral intake is the only method route for centchroman administration in humans. The two-compartmental model with first-order absorption has been used to describe centchroman kinetic behavior after its oral administration [46,49–54]. 4.1. Absorption Following a single 60-mg oral dose in three healthy females, centchroman was rapidly absorbed, with a maximum serum concentration (Cmax) varying from 117 to 129 ng/mL (Table 1), and was observed 4 h after drug ingestion [46]. However, in healthy subjects who received 30 mg of centchroman as oral tablets, it was shown that Cmax was 30.45 to 78.41 ng/mL after 3 to 8 h (Fig. 1). The serum concentration–time curve (AUC0–∞) averaged to 5199±1388 ng h/mL [49]. Intersubject variability in the absorption profile (Cmax, tmax and AUC0–∞) was demonstrated by an appropriate 2.6-fold difference between minimum and maximum values. These results compared well with those of Paliwal et al. [46] who investigated the pharmacokinetic parameters of centchroman. An insignificant difference was observed in the rates of absorption between the two single 30- and 60-mg doses. Moreover, mean Cmax and AUC after the 30-mg dose were approximately half of those observed with a single 60-mg dose indicating that these parameters are dose dependent [49]. In a relative bioavailability study of centchroman in 30mg tablets of Saheli (Hindustan Latex) and Centron (Torrent Pharmaceuticals India) in six healthy female subjects, a mean Cmax of 67.55 ng/mL was observed between the 4- and 8-h tablets from Saheli (Table 1) and was similar to the tablets from Centron [50]. The Cmax, tmax and AUC0–∞ of centchroman from either product were insignificantly different to the values reported earlier by Lal et al. [49] after a single 30-mg per oral dose of centchroman. Like the earlier study, there was considerable intersubject variation in the pharmacokinetic parameters of centchroman, but no
Fig. 1. Mean (±SD) serum concentration–time plot of centchroman in healthy female volunteers after a single 30-mg oral dose of centchroman [49].
statistically significant differences were observed. The relative bioavailability of Centron to Saheli tablets averaged to 101.97% [50]. Following multiple oral dosing of centchroman (30 mg twice a week for 12 weeks) in three women, Cmax varied from 40.91 to 69.29 ng/mL and occurred 6 to 8 h after the first 30-mg dose and was similar to that observed in normal females after a single 30-mg oral dose [51,52]. Repeated administration did not cause any significant difference in Cmax, tmax, AUCτ or Css between the first and 24th dose, indicating insignificant accumulation (AUC1992–2064 h/AUC0–72 h: 1.30±0.29) during multiple dosing (paired t test, pb.05). Ninety-five percent steady-state concentrations were reached after 3.98–6.3 doses of centchroman. It was also investigated whether the nursing females, although having a small sample size, show similar absorption and/or need adjustment of dose. In nursing females who received 30 mg of centchroman as oral tablets, serum Cmax ranged from 50.08 to 79.74 ng/mL and occurred
Table 1 Pharmacokinetic parameters (mean±SD) for oral centchroman in adults Dose
Healthy, nonlactating volunteers 60 mg 30 mg 30 mg twice a week for 12 weeks 60 mg a week loading dose (Day 1) followed by 30 mg weekly×4 weeks 30 mg (Day 1)+tetracycline 250 mg tds×3 days Healthy nursing females 30 mg
Absorption
Elimination
Reference
Cmax (ng/mL)
tmax (h)
AUC0–∞ (ng h/mL)
Cl/F (L/h)
t1/2 (h)
125.0±5.7 55.5±15.5 62.4±12.0 74.7±15.2
4.0±0.0 5.2±1.8 6.0±0.0 3.3±1.0
10705±3953 5199±1388 2453±922a 3828±1438b
0.10±0.03 0.14±0.04 0.69±0.43 0.17±0.05
172±5 165±49 94±24 148±102
[46], n=3 [49], n=11 [51], n=3 [59], n=6
75.2±20
2.9±1.2
5834±1534
4.8±2.5
153±53
[69], n=11
60.7±12.2
6.0±0.0
5519±1066
0.13±0.03
160±53
[53], n=4
Cmax=Peak concentration; tmax=time to peak concentration; AUC0–∞=area under the concentration–time curve from Time 0 to infinity; Cl/F=clearance; t1/2=elimination half-life. a 1992–2064 h. b 672–853 h.
278
J. Lal / Contraception 81 (2010) 275–280
at 6 h (Table 1). AUC0–∞ was 4160–6575 ng h/mL [53]. According to the authors, the kinetic characteristics in nursing female volunteers are comparable with those in healthy females and therefore the nursing females do not need adjustment of dose. In two nursing women who received multiple oral dosing of centchroman (30 mg twice a week for 12 weeks), steady-state serum concentrations were 53.07 and 46.44 ng/mL. Following the last 30-mg dose, the ratio AUCτ (1920–1992 h)/AUCτ (0–72 h) reaffirmed insignificant accumulation of the drug [54]. According to the authors, the reason for the small sample size is the monthlong sampling protocol due to the long half-life of centchroman and poor volunteer compliance with serial blood and/or milk measurement. 4.2. Distribution Centchroman is widely distributed within the body due to its high lipid solubility [46,49,50,52–54]. In healthy women, the apparent volume of distribution (Vd/F) was higher than the total body fluid and the mean residence time (MRT) was 128 days. Moreover, nursing females showed comparable Vd/F to that of nonnursing females treated orally. Therefore, breastfeeding does not appear to affect the distribution of this drug. Centchroman binds strongly to serum albumin in healthy subjects (∼90%) in the individual serum samples with intersubject variability in protein binding of centchroman. The binding increases with an increase in total protein content. This shows that centchroman may have saturation in binding at concentrations above 1 mcg/mL [55]. Such avid binding assumes great importance as the drug is administered in areas of the world where malnutrition and hypoalbuminemia are common, so in these females a decrease in plasma proteins and, consequently, a higher free fraction of centchroman could be expected. But these females will not need adjustment of doses as centchroman possesses excellent therapeutic index and has been well tolerated, without any hematological, biochemical or histopathological evidence of toxicity when administered at many times the contraceptive dose [5,25]. It exhibits low-affinity, high-capacity binding with plasma albumin in human with a Kd value of 13.19×10−6 M [55–58]. It does not compete with cortisol, estradiol, progesterone, testosterone, dihydrotestosterone or nonsteroidal estrogen agonist diethylstilbestrol or antagonists tamoxifen and nafoxidene, and is unlikely to displace steroids from specific steroid-binding plasma proteins [57], but in target tissues, e.g., the endometrium, it competes with estradiol for binding to estrogen receptor and shows an antiestrogenic activity [25]. Distribution of centchroman has also been determined in the target organ (endometrium) which could be critical in deciding its activity as this agent interferes with the process of implantation postfertilization by altering endometrial receptivity [25]. For this, the females of reproductive age were administered an oral tablet containing 30 mg of centchroman 4 to 6 h prior to hysterectomy. At the time of
hysterectomy, venous blood (∼5 mL) and the endometrium (5 to 10 g) were collected simultaneously from the subjects. The endometrium centchroman levels ranged from 93 to 223 ng/g (mean±SD: 152±39 ng/g) [48]. Thus, a relatively large amount of the drug reaches the endometrium within 4 to 6 h of drug ingestion. In earlier publications [49–54], a large intersubject variation in serum centchroman levels has also been observed. These differences between minimum and maximum values are probably the extremes of the expected intersubject variation and indicate the possibility of first-pass effect. However, a significant correlation (pb.01) between centchroman levels in the endometrium and serum demonstrated the dependence of endometrium uptake on serum concentrations. In addition, the y-intercept value of 1.93 indicated that the concentration of the drug in the endometrium at any time is approximately 1.93-fold greater than the corresponding concentration in serum. At the peak levels, the tissue-to-serum ratio of centchroman was found to be 2.8±0.6 (range, 2.0 to 4.1). The data also indicate that centchroman is rapidly absorbed and distributed to the target tissue after oral ingestion [48]. 4.3. Elimination Studies regarding the metabolism of centchroman in humans are scarce. In serum and milk, the demethylated metabolite (7-desmethyl centchroman) has been reported after the oral administration of centchroman to healthy volunteers [51,52,59]. However, unchanged centchroman recovered in rat feces accounted for ∼26% of the administered centchroman dose, thus indicating extensive metabolism [60,61]. This drug is extensively metabolized by rat liver homogenate [60,62,63]. The 2-12C-centchroman (specific activity: 2.93 mCi/mmol) is metabolized by rat liver homogenate in vitro to biologically active (7-desmethyl chroman, 2-desmethyl chroman and 2-monomethyl chroman) and inactive metabolites, with active metabolites contributing to estrogen agonistic and anti-implantation activities, while inactive metabolites accounting for its gradual metabolic disposition [62]. Interestingly, all the three biologically active metabolites constitute its demethylated products showing 100% anti-implantation activity at 0.25, 0.25 and 2 mg/kg oral doses, respectively [62]. Of these, 7-desmethyl centchroman has earlier been considered as the possible active metabolite of centchroman in vivo [60]. A marked increase in activity of hepatic microsomal aniline hydroxylase, aminopyrine N-demethylase, cytochrome P450 and cytochrome b5, indicating rapid disposal of the compound from the body, has also been observed in adult female rhesus monkeys treated with 25 mg/kg dose of centchroman 8 h before autopsy. No effect, however, has been observed on activity of any enzyme of hepatic microsomal mixed function oxygenase system at its singlecontraceptive (2.5 mg/kg) dose [64]. Systemic clearance (0.14±0.04 L/h per kilogram) was 1.5 times higher than renal plasma flow [65]; sites other than the kidney appear to be implicated in clearing the centchroman.
J. Lal / Contraception 81 (2010) 275–280
Finally, in the milk of healthy women administered 30 mg of centchroman as oral tablets, Cmax (70.72 ng/mL) was reached in 8.5 h [53]. On the basis of this information, a breast-fed child would receive an average dose of only 50.46 mcg/kg per week, corresponding to 7.43% per week, via milk. Another study showed that the average infant dose of centchroman via breast milk, assuming a weekly milk intake of 1.05 L/kg and 100% absorption, will not exceed 5% of the maternal dose per week which is less than 1% of the maternal dose per day. The milk-to-serum ratios were more than unity, typical of a basic compound, and were consistent [53,54,66– 68]. The steady-state drug concentration after a single dose may not be different from that after multiple doses, and thus neither will the amount of drug ingested by the infants via breast milk [53]. An infant dose per kilogram per day that is less than 10% of the maternal dose per kilogram is generally considered to be safe [68]. Thus, the authors believe that the amount of centchroman ingested by the infants via breast milk is unlikely to be of any physiological consequence to the infants and the authors did not recommend excluding breastfeeding mothers from mass centchroman therapies.
[7]
[8]
[9]
[10]
[11] [12]
[13]
4.4. Drug–drug interactions [14]
Pharmacokinetic interactions commonly occur via drugmetabolizing enzymes or drug transporters. Co-administration of tetracycline yielded significantly higher Cmax (35%) and a shorter time to reach Cmax (tmax) for centchroman (42%) than those obtained in the control group of females [69]. Inclusion of lactic acid bacillus spores in the regimen resulted in similar effects with increase in Cmax (47%) and AUC0–∞ (34%) of centchroman with a significant decrease in tmax. Other parameters such as half-life, apparent clearance, Vd/F and MRT of centchroman were not affected by either of the treatment.
[15] [16]
[17] [18]
[19]
Acknowledgments
[20]
The author expresses their gratitude to the director of Central Drug Research Institute, CSIR, Lucknow, India, for his encouragements. The author thanks Dr. Anila Dwivedi for her valuable suggestions. CDRI Communication No.: 7724.
[21]
References
[23]
[1] Ray S, Kamboj V, Grover P, Kar A, Anand N. A process for the synthesis of 2,2-disubstituted-3,4-diphenylchromans; 1975. Indian Patent Specification No. 129187. [2] WHO. Proposed international nonproprietary names: List 69. WHO Drug Inf 1993;7:87. [3] Nityanand S, Anand N. Centchroman: a nonsteroidal antifertility agent. FOGSI (Fed Obstet Gynaecol Soc, India) FOCUS 1996:8–10. [4] Nityanand S. Centchroman: current status as a contraceptive. Proc X Indian Conf Family Welfare Voluntary Sterilization, Jimpur, Pondicherry, India, August 19–21; 1994. p. 41–2. [5] Kamboj VP, Ray S, Dhawan BN. Centchroman. Drugs Today 1992;28:227–32. [6] Nityanand S, Wati C, Singh L, Srivastava JS, Kamboj VP. Clinical evaluation of centchroman: a new oral contraceptive. In: Puri CP,
[22]
[24] [25]
[26]
[27]
279
VanLook PFA, editors. Hormone antagonists for fertility regulation. Bombay: Indian Soc Study Reprod Fert, India; 1988. p. 223–30. Nityanand S, Kamboj VP, Wati C, et al. Contraceptive efficacy and safety of centchroman with biweekly-cum-weekly schedule. In: Puri CP, VanLook PFA, editors. Current concepts in fertility regulation and reproduction. New Delhi: Wiley Eastern Ltd; 1994. p. 61–8. Nityanand S, Gupta RC, Kamboj VP, Srivastava PK, Berry M. Centchroman: current status as a contraceptive. In: Dawn SC, Misra A, editors. Indian progress in family welfare: Clinical research on maternal and child health and contraception. Calcutta: Dawn Books; 1995. p. 26–31. Puri V, Kamboj VP, Chandra H, et al. Results of multicentric trial of centchroman. In: Dhawan BN, Agarwal KK, Arora RB, Parmar SS, editors. Pharmacology for health in Asia. Allied Publishers: New Delhi; 1988. p. 439–47. Rajpal M, Rajpal VK. Efficacy and safety of centchroman in clinical practice: a retrospective study. Proc X Indian Conf Family Welfare Voluntary Sterilization, Jimpur, Pondicherry, India, 19–21, August; 1994. p. 21. Rajan R. Contraceptive and non-contraceptive benefits of centchroman. Asian J Obstet Gynaecol 1996;1:65–71. Rajan R. Contraceptive and non-contraceptive benefits of centchroman. Proceedings of the International Meeting on Safe Motherhood, Guwahati, India; 1996. p. 94–9. Rajan R. Contraceptive and non-contraceptive benefits of centchroman. In: Rajan R, editor. Reproductive endocrinology. Jaypee Brothers: New Delhi; 1997. p. 487–97. Jordan VC. Biochemical pharmacology of antiestrogen action. Pharmacol Rev 1984;36:245–76. Grubb GS. Experimental methods of contraception. Curr Opin Obstet Gynecol 1991;3:491–5. Yuzpe AA. Post-coital contraception. In: Corson SL, Derman RJ, Tyrer LB, editors. Fertility control. Boston, MA: Little Brown and Company; 1985. p. 289–97. Macgregor JJ, Jordan VC. Basic guide to the mechanism of antiestrogen action. Pharm Rev 1998;50:151–96. Kamboj VP, Kar AB, Ray S, Grover PK, Anand N. Antifertility activity of 3-4-trans-2,2-dimethyl-3-phenyl-4-[4-(β-pyrolidinoethoxy) phenyl]-7-methoxychromans. Indian J Exp Biol 1971;9:103–5. Kamboj VP, Setty BS, Chandra H, Roy SK, Kar AB. Biological profile of centchroman- a new post-coital contraceptive. Indian J Exp Biol 1977;15:1141–50. Singh MM, Bhalla V, Wadhwa V, Kamboj VP. Effect of centchroman on tubal transport and pre-implantation embryonic developments in rats. J Reprod Fertil 1986;76:317–24. Singh MM, Kamboj VP. Fetal resorption in rats treated with an antiestrogen in relation to luteal phase nidatory estrogen secretion. Acta Endocr 1992;126:444–50. Singh MM, Sreenivasulu S, Kamboj VP. Duration of anti-implantation action of a triphenylethylene antiestrogen centchroman in adult female rats. J Reprod Fertil 1994;100:367–74. Indian Pharmacopoeia. Centchroman. Delhi: The Controller of Publications; 1996. p. 539–40. The Merck Index. In: Budavari S, editor. Centchroman. 12th ed. Whitehouse Station, NJ: 7 Merck Co. Inc; 1996. p. 327. Singh MM. Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone-related clinical disorders. Med Res Rev 2001;21:302–47. Trivedi RN, Chauhan SC, Dwivedi A, Maitra SC, Kamboj VP, Singh MM. Time related effects of a triphenylethylene antiestrogen on estrogen induced changes in uterine weight, estrogen receptors and endometrial sensitivity in immature rats. Contraception 1995;51: 367–79. Chauhan SC, Singh MM, Maitra SC, Kamboj VP. Inhibition of progesterone induced development of giant mitochondria in uterine glandular epithelial cells by an antiestrogen in rat. Contraception 1996;54:259–64.
280
J. Lal / Contraception 81 (2010) 275–280
[28] Singh MM, Chauhan SC, Maitra SC, Trivedi RN, Kamboj VP. Correlation of pinopod development on uterine luminal epithelial surface with hormonal events and endometrial sensitivity in rat. Eur J Endocr 1996;135:107–17. [29] Singh MM, Trivedi RN, Chauhan SC, Srivastava VML, Kamboj VP. Uterine estradiol and progesterone receptor concentration, activities of certain antioxidant enzymes and dehydrogenases and histoarchitecture in relation to time of secretion of nidatory estrogen and high endometrial sensitivity in rat. J Steroid Biochem Mol Biol 1996;59: 215–24. [30] Bansode FW, Chauhan SC, Makke A, Singh MM. Uterine luminal epithelial alkaline phosphatase activity and pinopod development in relation to endometrial sensitivity in rat. Contraception 1998;58: 61–8. [31] CDRI. Centchroman: antineoplastic, antiestrogen. Drugs Fut 1991;16: 654. [32] Iyer SS. India launches the new weekly contraceptive pill. Drug News Perspect 1991;4:228–9. [33] Misra NC, Nigam PK, Gupta R, Aggarwal AK, Kamboj VP. Centchroman—a nonsteroidal anticancer agent for advanced breast cancer—Phase II study. Int J Cancer 1989;43:781–3. [34] Piggott JM. 3,4-Diarylchromans for treatment of dermatitis. Zymogenetics, Seattle, WA, US Patent 5451603. [35] Labroo VM, Piggott JR, Bain SD, Methods for reducing bone loss using centchroman derivatives. Zymogenetics, Seattle, WA US Patent 5280040. [36] Bryant HU, Dodge JA, Methods for lowering cholesterol and inhibiting smooth muscle proliferation, restenosis, endometriosis, and uterine fibroid disease. Eli Lilly, Indianapolis, IN US Patent 5407955. [37] Nair RK, Sheyte TA, Munshi SR. Progestational and antiprogestational effects of centchroman in mouse and rabbit. Indian J Exp Biol 1977;15:1157–8. [38] Mehrotra PK, Nilsson BO. Ultrastructural effects of the nonsteroidal contraceptive centchroman on rat uterine luminal epithelium in early pregnancy. Int J Fertil 1984;29:44–53. [39] Roy SN, Kumari GL, Modoiya K, Prakash V, Ray S. Induction of ovulation in human with centchroman, a preliminary report. Fertil Steril 1976;27:1108–10. [40] Singh MM, Bhalla V, Wadhwa V, Kamboj VP. Effect of centchroman on tubal transport and preimplantation embryonic development in rats. J Reprod Fert 1986;76:317–24. [41] Labroo VM, Piggott JR, Bain SD. Methods for reducing bone loss using centchroman derivatives. Zymogenetics, Seattle, WA. US 5,280,040. [42] Piggott JR. 3,4-Diarylchromans for treatment of dermatitis. Zymogenetics, Seattle, WA. US 5,451,603. [43] Bryant HU, Dodge JA. Methods for lowering cholesterol and inhibiting smooth muscle proliferation, restenosis, endometriosis, and uterine fibroid disease. Eli Lilly Indianapolis, IN., US 5,407,955. [44] Williams JP, McDonald JM, McKenna MA, Jordan SE, Radding W, Blair HC. Differential effects of tamoxifen-like compounds on osteoclastic bone degradation, H(+)-ATPase activity, calmodulindependent cyclic nucleotide phosphodiesterase activity, and calmodulin binding. J Cell Biochem 1997;66:358–69. [45] Dwivedi A, Basu R, Chowdhury SR, Goyal N. Modulation of estrogen action during preimplantation period and in immature estradiol-primed rat uterus by anti-implantation agent, ormeloxifene. Contraception 2005;71:458–64. [46] Paliwal JK, Gupta RC, Grover PK, Asthana OP, Srivastava JS, Nityanand S. High-performance liquid chromatography (HPLC) determination of centchroman in human serum, and application to single-dose pharmacokinetics. Pharm Res 1989;6:1048–51. [47] Lal J, Paliwal JK, Grover PK, Gupta RC. Simultaneous liquid chromatographic determination of centchroman and its 7-demethylated metabolite in serum and milk. J Chromatogr Biomed Appl 1994;658: 193–7.
[48] Khurana M, Lal J, Kamboj M, Nityanand S, Kamboj VP, Gupta RC. Uptake of centchroman by human uterus. Clin Drug Invest 2002;22:715–8. [49] Lal J, Asthana OP, Nityanand S, Gupta RC. Pharmacokinetics of centchroman in healthy female subjects after oral administration. Contraception 1995;52:297–300. [50] Lal J, Nityanand S, Asthana OP, Gupta RC. Comparative bioavailability of two commercial centchroman tablets in healthy female subjects. Indian J Pharmacol 1996;28:32–4. [51] Gupta RC, Lal J, Nityanand S, Asthana OP. Dose-related differences in serum concentration of centchroman in female volunteers. Proc XXIX Ann Conf Indian Pharmacol Soc, Hyderabad, India; 1996. [52] Lal J, Nityanand S, Asthana OP, Gupta RC. Multiple-dose pharmacokinetics of centchroman in female volunteers. Indian J Pharmacol 1998;30:120. [53] Gupta RC, Nityanand S, Asthana OP, Lal J. Pharmacokinetics of centchroman in nursing women and passage into breast milk. Clin Drug Invest 1996;11:305–9. [54] Gupta RC, Nityanand S, Asthana OP, Lal J. Centchroman kinetics and disposition into breast milk. Proc 1st Ann Conf Indian Soc Chem Biol, Lucknow, India, 23–24 March; 1996. p. 93–100. [55] Khurana M, Paliwal JK, Kamboj VP, Gupta RC. Binding of centchroman as determined by charcoal adsorption method. Int J Pharm 1999;197:109–14. [56] Ratna S, Chandra G, Ray S, Roy SK. Centchroman: binding with plasma proteins of rat, rabbit, guinea pig, and rhesus monkey. Drug Dev Res 1991;24:285–91. [57] Agnihotri A, Srivastava AK, Kamboj VP. Characterization of centchroman binding protein in plasma of rhesus monkey (Macaca mulatta). J Med Primatol 1996;25:53–6. [58] Srivastava AK, Agnihotri A, Kamboj VP. Binding of centchroman—a nonsteroidal antifertility agent in human plasma proteins. Experientia 1984;40:465–6. [59] Lal J, Nityanand S, Asthana OP, Nagaraja NV, Gupta RC. Optimization of contraceptive dosage regimen of centchroman. Contraception 2001;63:47–51. [60] Paliwal JK, Gupta RC. Tissue distribution and pharmacokinetics of centchroman a new nonsteroidal postcoital contraceptive agent and its 7-desmethyl metabolite in female rats after a single oral dose. Drug Metab Dispos 1996;24:148–55. [61] Khurana M, Lal J, Singh MM, Paliwal JK, Kamboj VP, Gupta RC. Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of centchroman in rats. Contraception 2002;66:47–56. [62] Ratna S, Roy SK, Ray S, et al. Centchroman: in vitro metabolism by rat liver homogenate. Drug Dev Res 1986;7:173–8. [63] Kole PL, Ray S. Synthesis of trans-2,2-dimethyl-3-phenyl-4-(p-βpyrrolidinoethoxy) phenyl-7-methoxy-(2-12C)chroman. J Labelled Compd Radiopharm 1978;16:373–6. [64] Mishra NC, Ray S, Roy SK. Influence of centchroman on some hepatic microsomal enzymes in female rhesus monkeys. Med Sci Res 1990;18:881–2. [65] Ganong WF. Review of Medical Physiology. California: Lange Medical Publications; 1985. p. 575. [66] Paliwal JK, Grover PK, Asthana OP, Nityanand S, Gupta RC. Excretion of centchroman in breast milk. Br J Clin Pharmacol 1994;38:485–6. [67] Gupta RC, Paliwal JK, Nityanand S, Asthana OP, Lal J. Centchroman: a new nonsteroidal oral contraceptive in human milk. Contraception 1995;52:301–5. [68] Atkinson HC, Begg EJ, Darlow BA. Guide to safety of drugs in human milk. Clinical Pharmacokinetics Drug Data Handbook, 4. Sydney: Adis Press; 1990. p. 125–64. [69] Khurana M, Lal J, Kamboj VP, Nityanand S, Gupta RC. Pharmacokinetic interaction of tetracycline with centchroman in healthy female volunteers. Drugs R D 2003;4:293–9.
Review article
Clinical pharmacokinetics and interaction of centchroman — A mini review☆ Jawahar Lal⁎
Pharmacokinetics and Metabolism Division, Central Drug Research Institute, CSIR, Lucknow 226001, India Received 12 February 2009; revised 12 November 2009; accepted 19 November 2009
Abstract This article provides a brief review of the information available regarding the published pharmacokinetics data for the nonsteroidal, oncea-week oral contraceptive, centchroman (INN: ormeloxifene). This agent is a unique need-oriented contraceptive agent which is included in the National Family Welfare Programme of India. Since 1991, centchroman has been used as a need-oriented contraceptive and is being given for treating dysfunctional bleeding of the uterus. Information regarding absorption, tissue distribution, elimination and kinetic interactions is discussed. © 2010 Elsevier Inc. All rights reserved. Keywords: Centchroman; Ormeloxifene; Selective estrogen receptor modulator; Pharmacokinetics; Drug–drug interaction
1. Introduction DL-Centchroman (INN: ormeloxifene; trans-7-methoxy2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidinoethoxy) phenyl] chroman hydrochloride) is a nonsteroidal selective estrogen receptor modulator and once-a-week oral contraceptive agent developed by the Indian Central Drug Research Institute (Lucknow, India) [1–17]. This agent's contraceptive activity is well established in rodents and primates, wherein a single oral dose of centchroman within 24 h of coitus successfully prevents pregnancy in rats, dogs and rhesus monkeys, and wherein the antifertility effect of centchroman is promptly reversible [5,18,19]. Centchroman inhibits implantation via inhibition of endometrial receptivity to blastocyst signals by antagonism of the action of nidatory estrogen, without altering the concentration or secretion pattern of nidatory estrogen and progesterone, hypothalamo-pituitary-ovarian axis, follicle maturation, ovulation, mating behavior, gamete transport or fertilization, and preimplantation development of embryos [20–30]. Clinically, centchroman has been reported to provide good pregnancy protection in women in postcoital as well as ☆
There was no funding provided for this study. ⁎ Tel.: +91 522 2612411 18x4406; fax: +91 522 2623938/2623405. E-mail addresses: [email protected], [email protected].
0010-7824/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2009.11.007
weekly regimens [6,9] and is marketed in India as a contraceptive pill [5]. Centchroman was introduced in Delhi in July 1991, marketed in India in 1992 as Saheli and Choice-7 (Hindustan Latex, Ltd., Thiruvananthapuram, India) and Centron (Torrent Pharmaceuticals India, Ltd., Ahmedabad, India) and included in the National Family Welfare Programme in 1995 [3,4,31,32]. Centchroman is a unique need-oriented contraceptive being effective when taken immediately after coitus or routinely as a weekly pill and has the advantage of less frequent administration than oral contraceptives [3–6,8–17]. Centchroman is effective for contraception in a 30- and 60-mg once-a-week postcoital dose regimen [5]. This regimen (30 mg once a week) suffered from some early failures (pregnancies, most of which happened during the initial period of its use) possibly due to inadequate circulating levels before attaining a steady state. To reduce the failure rates, centchroman is, at present, recommended to be used with an initial twice-a-week 30-mg dose for 12 weeks followed by a 30-mg once-a-week regimen [5,23,24]. Centchroman with the trade name of Sevista is nowadays being manufactured by Torrent Pharmaceuticals India for treating dysfunctional bleeding of the uterus. Due to its potent anti-estrogenic and weak estrogenic activities [5,6,9,19,22,26–30], it is also effective against advanced breast cancer [33] and may be therapeutically effective for
276
J. Lal / Contraception 81 (2010) 275–280
other clinical conditions such as dermatitis [34], osteoporosis [35], restenosis, endometriosis and uterine fibroids [36]. Centchroman as a racemate has been found to be a potent cholesterol-lowering pharmaceutical resulting in a significant decrease in serum concentrations [36]. Due to the widespread and long-term clinical use of this drug in humans, knowledge of centchroman pharmacokinetic behavior becomes essential. Nevertheless, little is known about the pharmacokinetics and interactions of centchroman in humans compared to animals. Thus, in this article, the literature is reviewed concerning the absorption, distribution, metabolism and excretion of centchroman in human, as well as the interactions of the drug. 2. Pharmacological properties In humans, centchroman behaves as a potent antiestrogen but also has weak estrogenic and antiprogestational actions [37,38]. Roy et al. [39] reported that centchroman can induce ovulation when given chronically in daily doses of 15, 30 or 60 mg for 10 to 20 days to women who are not ovulating. On weekly single-dose (30–60 mg) administration to healthy, ovulating women for contraception, centchroman does not alter basal or peak gonadotropin (FSH/LH) secretion or production of estradiol and progesterone. In addition, it does not block ovulation. At this dosage and frequency of administration, the reproductive endocrine effects of the drug remain to slightly increase the transport of the zygote through the oviducts, accelerate blastocyst formation and suppress uterine endometrial proliferation and decidualization. Apparently, the combined effect of these actions is capable of creating sufficient asynchrony between the developing zygote and endometrial maturation to prevent implantation [40]. Centchroman inhibits implantation via inhibition of endometrial receptivity to blastocyst signals by antagonism of action of nidatory estrogen, without altering the concentration or secretion pattern of nidatory estrogen and progesterone, hypothalamo-pituitary-ovarian axis, follicle maturation, ovulation, mating behavior, gamete transport or fertilization, and preimplantation development of embryos [20–30]. Centchroman manifests its contraceptive activity primarily by producing asynchrony between ovum transport and uterine preparation for its reception and does not affect the hypothalamic-pituitary-ovarian axis or the embryo. The antifertility effect is readily reversible and subsequent pregnancy is normal. Centchroman suppresses the receptors in the reproductive organs like the ovaries, uterus and breasts. But it stimulates the estrogen receptors of other organs like the bones. So, while it acts as a birth control pill [5], it may prevent breast cancer [33] and may be therapeutically effective for other clinical conditions such as osteoporosis [41], dermatitis [42], restenosis, endometriosis and uterine fibroids [43]. Centchroman inhibits osteoclast degradation by 30%, calmodulin-dependent cyclic nucleotide phosphodiesterase and the effects are calcium dependent [44]. Centchro-
man, in addition to its competitive antagonism at the estrogen receptor level, promotes the conversion of intracellular estradiol (E2) to estrone (E1), a biologically less active form, by activating 17-β-hydroxysteroid dehydrogenase II, thus decreasing the estrogen receptor pool. Moreover, centchroman causes indirect anti-progestational effects in the uterus by virtue of its anti-estrogenic profile rather than by blocking the progesterone receptors [45]. 3. Analytical methodology Centchroman has been quantitated in serum by liquid chromatography with fluorescence detection set at an excitation and emission wavelength of 280 and 310 nm, respectively [46]. The technique uses 1–2 mL of serum and exhibited a lower limit of quantitation (LOQ) of 2 ng/mL. In addition to plasma levels, Lal et al. [47] have validated a method for the unlabelled parent drug and its metabolite (centchroman and its 7-desmethylated metabolite) in serum and milk using 0.5 mL of the biomatrices and fluorescence detection with a LOQ of 1 and 2.5 ng/mL, respectively. Briefly, serum (0.5 mL) was basified with potassium hydroxide solution (25 μL, 1 M) and then extracted twice with diethyl ether. The combined organic layer was evaporated to dryness under vacuum, and the dried residue was reconstituted in 0.1 mL of mobile phase and analyzed by HPLC equipped with a Spheri 5-μm Cyano column preceded with a guard column. The detection was performed using a fluorescence detector set at excitation (280 nm) and emission (310 nm) wavelengths. Unknown concentrations of centchroman and one of its major metabolites were interpolated from the respective serum standard curves drawn. Milk samples were subjected to protein precipitation with acetonitrile, and the supernatant was evaporated to dryness before being extracted with diethyl ether. The dried extract was reconstituted in 0.1 mL mobile phase and analyzed by HPLC using fluorescence detection. In addition, Khurana et al. [48] developed a method for determination of centchroman and 7desmethyl centchroman in the human uterus using HPLC and fluorescence detection with a LOQ of 10 ng/g. Briefly, an endometrium sample (0.1 g) was minced with scissors and homogenized in 0.75 mL of phosphate buffer (10 mmol/L, pH 3) and rehomogenised upon addition of 1.75 mL acetonitrile. After evaporation of the supernatant (2 mL), the residue was dissolved in 0.2 mL potassium hydroxide (0.2 mol/L) and extracted twice with 2 mL of extraction solvent (60% n-hexane in ethyl acetate). The combined organic layer was evaporated to dryness and the dried extract was reconstituted in 0.1 mL mobile phase and analyzed by HPLC using fluorescence detection. 4. Pharmacokinetics The pharmacokinetic properties of centchroman have been investigated in healthy female volunteers and nursing
J. Lal / Contraception 81 (2010) 275–280
277
mothers. The studies have used a liquid chromatographic method. Oral intake is the only method route for centchroman administration in humans. The two-compartmental model with first-order absorption has been used to describe centchroman kinetic behavior after its oral administration [46,49–54]. 4.1. Absorption Following a single 60-mg oral dose in three healthy females, centchroman was rapidly absorbed, with a maximum serum concentration (Cmax) varying from 117 to 129 ng/mL (Table 1), and was observed 4 h after drug ingestion [46]. However, in healthy subjects who received 30 mg of centchroman as oral tablets, it was shown that Cmax was 30.45 to 78.41 ng/mL after 3 to 8 h (Fig. 1). The serum concentration–time curve (AUC0–∞) averaged to 5199±1388 ng h/mL [49]. Intersubject variability in the absorption profile (Cmax, tmax and AUC0–∞) was demonstrated by an appropriate 2.6-fold difference between minimum and maximum values. These results compared well with those of Paliwal et al. [46] who investigated the pharmacokinetic parameters of centchroman. An insignificant difference was observed in the rates of absorption between the two single 30- and 60-mg doses. Moreover, mean Cmax and AUC after the 30-mg dose were approximately half of those observed with a single 60-mg dose indicating that these parameters are dose dependent [49]. In a relative bioavailability study of centchroman in 30mg tablets of Saheli (Hindustan Latex) and Centron (Torrent Pharmaceuticals India) in six healthy female subjects, a mean Cmax of 67.55 ng/mL was observed between the 4- and 8-h tablets from Saheli (Table 1) and was similar to the tablets from Centron [50]. The Cmax, tmax and AUC0–∞ of centchroman from either product were insignificantly different to the values reported earlier by Lal et al. [49] after a single 30-mg per oral dose of centchroman. Like the earlier study, there was considerable intersubject variation in the pharmacokinetic parameters of centchroman, but no
Fig. 1. Mean (±SD) serum concentration–time plot of centchroman in healthy female volunteers after a single 30-mg oral dose of centchroman [49].
statistically significant differences were observed. The relative bioavailability of Centron to Saheli tablets averaged to 101.97% [50]. Following multiple oral dosing of centchroman (30 mg twice a week for 12 weeks) in three women, Cmax varied from 40.91 to 69.29 ng/mL and occurred 6 to 8 h after the first 30-mg dose and was similar to that observed in normal females after a single 30-mg oral dose [51,52]. Repeated administration did not cause any significant difference in Cmax, tmax, AUCτ or Css between the first and 24th dose, indicating insignificant accumulation (AUC1992–2064 h/AUC0–72 h: 1.30±0.29) during multiple dosing (paired t test, pb.05). Ninety-five percent steady-state concentrations were reached after 3.98–6.3 doses of centchroman. It was also investigated whether the nursing females, although having a small sample size, show similar absorption and/or need adjustment of dose. In nursing females who received 30 mg of centchroman as oral tablets, serum Cmax ranged from 50.08 to 79.74 ng/mL and occurred
Table 1 Pharmacokinetic parameters (mean±SD) for oral centchroman in adults Dose
Healthy, nonlactating volunteers 60 mg 30 mg 30 mg twice a week for 12 weeks 60 mg a week loading dose (Day 1) followed by 30 mg weekly×4 weeks 30 mg (Day 1)+tetracycline 250 mg tds×3 days Healthy nursing females 30 mg
Absorption
Elimination
Reference
Cmax (ng/mL)
tmax (h)
AUC0–∞ (ng h/mL)
Cl/F (L/h)
t1/2 (h)
125.0±5.7 55.5±15.5 62.4±12.0 74.7±15.2
4.0±0.0 5.2±1.8 6.0±0.0 3.3±1.0
10705±3953 5199±1388 2453±922a 3828±1438b
0.10±0.03 0.14±0.04 0.69±0.43 0.17±0.05
172±5 165±49 94±24 148±102
[46], n=3 [49], n=11 [51], n=3 [59], n=6
75.2±20
2.9±1.2
5834±1534
4.8±2.5
153±53
[69], n=11
60.7±12.2
6.0±0.0
5519±1066
0.13±0.03
160±53
[53], n=4
Cmax=Peak concentration; tmax=time to peak concentration; AUC0–∞=area under the concentration–time curve from Time 0 to infinity; Cl/F=clearance; t1/2=elimination half-life. a 1992–2064 h. b 672–853 h.
278
J. Lal / Contraception 81 (2010) 275–280
at 6 h (Table 1). AUC0–∞ was 4160–6575 ng h/mL [53]. According to the authors, the kinetic characteristics in nursing female volunteers are comparable with those in healthy females and therefore the nursing females do not need adjustment of dose. In two nursing women who received multiple oral dosing of centchroman (30 mg twice a week for 12 weeks), steady-state serum concentrations were 53.07 and 46.44 ng/mL. Following the last 30-mg dose, the ratio AUCτ (1920–1992 h)/AUCτ (0–72 h) reaffirmed insignificant accumulation of the drug [54]. According to the authors, the reason for the small sample size is the monthlong sampling protocol due to the long half-life of centchroman and poor volunteer compliance with serial blood and/or milk measurement. 4.2. Distribution Centchroman is widely distributed within the body due to its high lipid solubility [46,49,50,52–54]. In healthy women, the apparent volume of distribution (Vd/F) was higher than the total body fluid and the mean residence time (MRT) was 128 days. Moreover, nursing females showed comparable Vd/F to that of nonnursing females treated orally. Therefore, breastfeeding does not appear to affect the distribution of this drug. Centchroman binds strongly to serum albumin in healthy subjects (∼90%) in the individual serum samples with intersubject variability in protein binding of centchroman. The binding increases with an increase in total protein content. This shows that centchroman may have saturation in binding at concentrations above 1 mcg/mL [55]. Such avid binding assumes great importance as the drug is administered in areas of the world where malnutrition and hypoalbuminemia are common, so in these females a decrease in plasma proteins and, consequently, a higher free fraction of centchroman could be expected. But these females will not need adjustment of doses as centchroman possesses excellent therapeutic index and has been well tolerated, without any hematological, biochemical or histopathological evidence of toxicity when administered at many times the contraceptive dose [5,25]. It exhibits low-affinity, high-capacity binding with plasma albumin in human with a Kd value of 13.19×10−6 M [55–58]. It does not compete with cortisol, estradiol, progesterone, testosterone, dihydrotestosterone or nonsteroidal estrogen agonist diethylstilbestrol or antagonists tamoxifen and nafoxidene, and is unlikely to displace steroids from specific steroid-binding plasma proteins [57], but in target tissues, e.g., the endometrium, it competes with estradiol for binding to estrogen receptor and shows an antiestrogenic activity [25]. Distribution of centchroman has also been determined in the target organ (endometrium) which could be critical in deciding its activity as this agent interferes with the process of implantation postfertilization by altering endometrial receptivity [25]. For this, the females of reproductive age were administered an oral tablet containing 30 mg of centchroman 4 to 6 h prior to hysterectomy. At the time of
hysterectomy, venous blood (∼5 mL) and the endometrium (5 to 10 g) were collected simultaneously from the subjects. The endometrium centchroman levels ranged from 93 to 223 ng/g (mean±SD: 152±39 ng/g) [48]. Thus, a relatively large amount of the drug reaches the endometrium within 4 to 6 h of drug ingestion. In earlier publications [49–54], a large intersubject variation in serum centchroman levels has also been observed. These differences between minimum and maximum values are probably the extremes of the expected intersubject variation and indicate the possibility of first-pass effect. However, a significant correlation (pb.01) between centchroman levels in the endometrium and serum demonstrated the dependence of endometrium uptake on serum concentrations. In addition, the y-intercept value of 1.93 indicated that the concentration of the drug in the endometrium at any time is approximately 1.93-fold greater than the corresponding concentration in serum. At the peak levels, the tissue-to-serum ratio of centchroman was found to be 2.8±0.6 (range, 2.0 to 4.1). The data also indicate that centchroman is rapidly absorbed and distributed to the target tissue after oral ingestion [48]. 4.3. Elimination Studies regarding the metabolism of centchroman in humans are scarce. In serum and milk, the demethylated metabolite (7-desmethyl centchroman) has been reported after the oral administration of centchroman to healthy volunteers [51,52,59]. However, unchanged centchroman recovered in rat feces accounted for ∼26% of the administered centchroman dose, thus indicating extensive metabolism [60,61]. This drug is extensively metabolized by rat liver homogenate [60,62,63]. The 2-12C-centchroman (specific activity: 2.93 mCi/mmol) is metabolized by rat liver homogenate in vitro to biologically active (7-desmethyl chroman, 2-desmethyl chroman and 2-monomethyl chroman) and inactive metabolites, with active metabolites contributing to estrogen agonistic and anti-implantation activities, while inactive metabolites accounting for its gradual metabolic disposition [62]. Interestingly, all the three biologically active metabolites constitute its demethylated products showing 100% anti-implantation activity at 0.25, 0.25 and 2 mg/kg oral doses, respectively [62]. Of these, 7-desmethyl centchroman has earlier been considered as the possible active metabolite of centchroman in vivo [60]. A marked increase in activity of hepatic microsomal aniline hydroxylase, aminopyrine N-demethylase, cytochrome P450 and cytochrome b5, indicating rapid disposal of the compound from the body, has also been observed in adult female rhesus monkeys treated with 25 mg/kg dose of centchroman 8 h before autopsy. No effect, however, has been observed on activity of any enzyme of hepatic microsomal mixed function oxygenase system at its singlecontraceptive (2.5 mg/kg) dose [64]. Systemic clearance (0.14±0.04 L/h per kilogram) was 1.5 times higher than renal plasma flow [65]; sites other than the kidney appear to be implicated in clearing the centchroman.
J. Lal / Contraception 81 (2010) 275–280
Finally, in the milk of healthy women administered 30 mg of centchroman as oral tablets, Cmax (70.72 ng/mL) was reached in 8.5 h [53]. On the basis of this information, a breast-fed child would receive an average dose of only 50.46 mcg/kg per week, corresponding to 7.43% per week, via milk. Another study showed that the average infant dose of centchroman via breast milk, assuming a weekly milk intake of 1.05 L/kg and 100% absorption, will not exceed 5% of the maternal dose per week which is less than 1% of the maternal dose per day. The milk-to-serum ratios were more than unity, typical of a basic compound, and were consistent [53,54,66– 68]. The steady-state drug concentration after a single dose may not be different from that after multiple doses, and thus neither will the amount of drug ingested by the infants via breast milk [53]. An infant dose per kilogram per day that is less than 10% of the maternal dose per kilogram is generally considered to be safe [68]. Thus, the authors believe that the amount of centchroman ingested by the infants via breast milk is unlikely to be of any physiological consequence to the infants and the authors did not recommend excluding breastfeeding mothers from mass centchroman therapies.
[7]
[8]
[9]
[10]
[11] [12]
[13]
4.4. Drug–drug interactions [14]
Pharmacokinetic interactions commonly occur via drugmetabolizing enzymes or drug transporters. Co-administration of tetracycline yielded significantly higher Cmax (35%) and a shorter time to reach Cmax (tmax) for centchroman (42%) than those obtained in the control group of females [69]. Inclusion of lactic acid bacillus spores in the regimen resulted in similar effects with increase in Cmax (47%) and AUC0–∞ (34%) of centchroman with a significant decrease in tmax. Other parameters such as half-life, apparent clearance, Vd/F and MRT of centchroman were not affected by either of the treatment.
[15] [16]
[17] [18]
[19]
Acknowledgments
[20]
The author expresses their gratitude to the director of Central Drug Research Institute, CSIR, Lucknow, India, for his encouragements. The author thanks Dr. Anila Dwivedi for her valuable suggestions. CDRI Communication No.: 7724.
[21]
References
[23]
[1] Ray S, Kamboj V, Grover P, Kar A, Anand N. A process for the synthesis of 2,2-disubstituted-3,4-diphenylchromans; 1975. Indian Patent Specification No. 129187. [2] WHO. Proposed international nonproprietary names: List 69. WHO Drug Inf 1993;7:87. [3] Nityanand S, Anand N. Centchroman: a nonsteroidal antifertility agent. FOGSI (Fed Obstet Gynaecol Soc, India) FOCUS 1996:8–10. [4] Nityanand S. Centchroman: current status as a contraceptive. Proc X Indian Conf Family Welfare Voluntary Sterilization, Jimpur, Pondicherry, India, August 19–21; 1994. p. 41–2. [5] Kamboj VP, Ray S, Dhawan BN. Centchroman. Drugs Today 1992;28:227–32. [6] Nityanand S, Wati C, Singh L, Srivastava JS, Kamboj VP. Clinical evaluation of centchroman: a new oral contraceptive. In: Puri CP,
[22]
[24] [25]
[26]
[27]
279
VanLook PFA, editors. Hormone antagonists for fertility regulation. Bombay: Indian Soc Study Reprod Fert, India; 1988. p. 223–30. Nityanand S, Kamboj VP, Wati C, et al. Contraceptive efficacy and safety of centchroman with biweekly-cum-weekly schedule. In: Puri CP, VanLook PFA, editors. Current concepts in fertility regulation and reproduction. New Delhi: Wiley Eastern Ltd; 1994. p. 61–8. Nityanand S, Gupta RC, Kamboj VP, Srivastava PK, Berry M. Centchroman: current status as a contraceptive. In: Dawn SC, Misra A, editors. Indian progress in family welfare: Clinical research on maternal and child health and contraception. Calcutta: Dawn Books; 1995. p. 26–31. Puri V, Kamboj VP, Chandra H, et al. Results of multicentric trial of centchroman. In: Dhawan BN, Agarwal KK, Arora RB, Parmar SS, editors. Pharmacology for health in Asia. Allied Publishers: New Delhi; 1988. p. 439–47. Rajpal M, Rajpal VK. Efficacy and safety of centchroman in clinical practice: a retrospective study. Proc X Indian Conf Family Welfare Voluntary Sterilization, Jimpur, Pondicherry, India, 19–21, August; 1994. p. 21. Rajan R. Contraceptive and non-contraceptive benefits of centchroman. Asian J Obstet Gynaecol 1996;1:65–71. Rajan R. Contraceptive and non-contraceptive benefits of centchroman. Proceedings of the International Meeting on Safe Motherhood, Guwahati, India; 1996. p. 94–9. Rajan R. Contraceptive and non-contraceptive benefits of centchroman. In: Rajan R, editor. Reproductive endocrinology. Jaypee Brothers: New Delhi; 1997. p. 487–97. Jordan VC. Biochemical pharmacology of antiestrogen action. Pharmacol Rev 1984;36:245–76. Grubb GS. Experimental methods of contraception. Curr Opin Obstet Gynecol 1991;3:491–5. Yuzpe AA. Post-coital contraception. In: Corson SL, Derman RJ, Tyrer LB, editors. Fertility control. Boston, MA: Little Brown and Company; 1985. p. 289–97. Macgregor JJ, Jordan VC. Basic guide to the mechanism of antiestrogen action. Pharm Rev 1998;50:151–96. Kamboj VP, Kar AB, Ray S, Grover PK, Anand N. Antifertility activity of 3-4-trans-2,2-dimethyl-3-phenyl-4-[4-(β-pyrolidinoethoxy) phenyl]-7-methoxychromans. Indian J Exp Biol 1971;9:103–5. Kamboj VP, Setty BS, Chandra H, Roy SK, Kar AB. Biological profile of centchroman- a new post-coital contraceptive. Indian J Exp Biol 1977;15:1141–50. Singh MM, Bhalla V, Wadhwa V, Kamboj VP. Effect of centchroman on tubal transport and pre-implantation embryonic developments in rats. J Reprod Fertil 1986;76:317–24. Singh MM, Kamboj VP. Fetal resorption in rats treated with an antiestrogen in relation to luteal phase nidatory estrogen secretion. Acta Endocr 1992;126:444–50. Singh MM, Sreenivasulu S, Kamboj VP. Duration of anti-implantation action of a triphenylethylene antiestrogen centchroman in adult female rats. J Reprod Fertil 1994;100:367–74. Indian Pharmacopoeia. Centchroman. Delhi: The Controller of Publications; 1996. p. 539–40. The Merck Index. In: Budavari S, editor. Centchroman. 12th ed. Whitehouse Station, NJ: 7 Merck Co. Inc; 1996. p. 327. Singh MM. Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone-related clinical disorders. Med Res Rev 2001;21:302–47. Trivedi RN, Chauhan SC, Dwivedi A, Maitra SC, Kamboj VP, Singh MM. Time related effects of a triphenylethylene antiestrogen on estrogen induced changes in uterine weight, estrogen receptors and endometrial sensitivity in immature rats. Contraception 1995;51: 367–79. Chauhan SC, Singh MM, Maitra SC, Kamboj VP. Inhibition of progesterone induced development of giant mitochondria in uterine glandular epithelial cells by an antiestrogen in rat. Contraception 1996;54:259–64.
280
J. Lal / Contraception 81 (2010) 275–280
[28] Singh MM, Chauhan SC, Maitra SC, Trivedi RN, Kamboj VP. Correlation of pinopod development on uterine luminal epithelial surface with hormonal events and endometrial sensitivity in rat. Eur J Endocr 1996;135:107–17. [29] Singh MM, Trivedi RN, Chauhan SC, Srivastava VML, Kamboj VP. Uterine estradiol and progesterone receptor concentration, activities of certain antioxidant enzymes and dehydrogenases and histoarchitecture in relation to time of secretion of nidatory estrogen and high endometrial sensitivity in rat. J Steroid Biochem Mol Biol 1996;59: 215–24. [30] Bansode FW, Chauhan SC, Makke A, Singh MM. Uterine luminal epithelial alkaline phosphatase activity and pinopod development in relation to endometrial sensitivity in rat. Contraception 1998;58: 61–8. [31] CDRI. Centchroman: antineoplastic, antiestrogen. Drugs Fut 1991;16: 654. [32] Iyer SS. India launches the new weekly contraceptive pill. Drug News Perspect 1991;4:228–9. [33] Misra NC, Nigam PK, Gupta R, Aggarwal AK, Kamboj VP. Centchroman—a nonsteroidal anticancer agent for advanced breast cancer—Phase II study. Int J Cancer 1989;43:781–3. [34] Piggott JM. 3,4-Diarylchromans for treatment of dermatitis. Zymogenetics, Seattle, WA, US Patent 5451603. [35] Labroo VM, Piggott JR, Bain SD, Methods for reducing bone loss using centchroman derivatives. Zymogenetics, Seattle, WA US Patent 5280040. [36] Bryant HU, Dodge JA, Methods for lowering cholesterol and inhibiting smooth muscle proliferation, restenosis, endometriosis, and uterine fibroid disease. Eli Lilly, Indianapolis, IN US Patent 5407955. [37] Nair RK, Sheyte TA, Munshi SR. Progestational and antiprogestational effects of centchroman in mouse and rabbit. Indian J Exp Biol 1977;15:1157–8. [38] Mehrotra PK, Nilsson BO. Ultrastructural effects of the nonsteroidal contraceptive centchroman on rat uterine luminal epithelium in early pregnancy. Int J Fertil 1984;29:44–53. [39] Roy SN, Kumari GL, Modoiya K, Prakash V, Ray S. Induction of ovulation in human with centchroman, a preliminary report. Fertil Steril 1976;27:1108–10. [40] Singh MM, Bhalla V, Wadhwa V, Kamboj VP. Effect of centchroman on tubal transport and preimplantation embryonic development in rats. J Reprod Fert 1986;76:317–24. [41] Labroo VM, Piggott JR, Bain SD. Methods for reducing bone loss using centchroman derivatives. Zymogenetics, Seattle, WA. US 5,280,040. [42] Piggott JR. 3,4-Diarylchromans for treatment of dermatitis. Zymogenetics, Seattle, WA. US 5,451,603. [43] Bryant HU, Dodge JA. Methods for lowering cholesterol and inhibiting smooth muscle proliferation, restenosis, endometriosis, and uterine fibroid disease. Eli Lilly Indianapolis, IN., US 5,407,955. [44] Williams JP, McDonald JM, McKenna MA, Jordan SE, Radding W, Blair HC. Differential effects of tamoxifen-like compounds on osteoclastic bone degradation, H(+)-ATPase activity, calmodulindependent cyclic nucleotide phosphodiesterase activity, and calmodulin binding. J Cell Biochem 1997;66:358–69. [45] Dwivedi A, Basu R, Chowdhury SR, Goyal N. Modulation of estrogen action during preimplantation period and in immature estradiol-primed rat uterus by anti-implantation agent, ormeloxifene. Contraception 2005;71:458–64. [46] Paliwal JK, Gupta RC, Grover PK, Asthana OP, Srivastava JS, Nityanand S. High-performance liquid chromatography (HPLC) determination of centchroman in human serum, and application to single-dose pharmacokinetics. Pharm Res 1989;6:1048–51. [47] Lal J, Paliwal JK, Grover PK, Gupta RC. Simultaneous liquid chromatographic determination of centchroman and its 7-demethylated metabolite in serum and milk. J Chromatogr Biomed Appl 1994;658: 193–7.
[48] Khurana M, Lal J, Kamboj M, Nityanand S, Kamboj VP, Gupta RC. Uptake of centchroman by human uterus. Clin Drug Invest 2002;22:715–8. [49] Lal J, Asthana OP, Nityanand S, Gupta RC. Pharmacokinetics of centchroman in healthy female subjects after oral administration. Contraception 1995;52:297–300. [50] Lal J, Nityanand S, Asthana OP, Gupta RC. Comparative bioavailability of two commercial centchroman tablets in healthy female subjects. Indian J Pharmacol 1996;28:32–4. [51] Gupta RC, Lal J, Nityanand S, Asthana OP. Dose-related differences in serum concentration of centchroman in female volunteers. Proc XXIX Ann Conf Indian Pharmacol Soc, Hyderabad, India; 1996. [52] Lal J, Nityanand S, Asthana OP, Gupta RC. Multiple-dose pharmacokinetics of centchroman in female volunteers. Indian J Pharmacol 1998;30:120. [53] Gupta RC, Nityanand S, Asthana OP, Lal J. Pharmacokinetics of centchroman in nursing women and passage into breast milk. Clin Drug Invest 1996;11:305–9. [54] Gupta RC, Nityanand S, Asthana OP, Lal J. Centchroman kinetics and disposition into breast milk. Proc 1st Ann Conf Indian Soc Chem Biol, Lucknow, India, 23–24 March; 1996. p. 93–100. [55] Khurana M, Paliwal JK, Kamboj VP, Gupta RC. Binding of centchroman as determined by charcoal adsorption method. Int J Pharm 1999;197:109–14. [56] Ratna S, Chandra G, Ray S, Roy SK. Centchroman: binding with plasma proteins of rat, rabbit, guinea pig, and rhesus monkey. Drug Dev Res 1991;24:285–91. [57] Agnihotri A, Srivastava AK, Kamboj VP. Characterization of centchroman binding protein in plasma of rhesus monkey (Macaca mulatta). J Med Primatol 1996;25:53–6. [58] Srivastava AK, Agnihotri A, Kamboj VP. Binding of centchroman—a nonsteroidal antifertility agent in human plasma proteins. Experientia 1984;40:465–6. [59] Lal J, Nityanand S, Asthana OP, Nagaraja NV, Gupta RC. Optimization of contraceptive dosage regimen of centchroman. Contraception 2001;63:47–51. [60] Paliwal JK, Gupta RC. Tissue distribution and pharmacokinetics of centchroman a new nonsteroidal postcoital contraceptive agent and its 7-desmethyl metabolite in female rats after a single oral dose. Drug Metab Dispos 1996;24:148–55. [61] Khurana M, Lal J, Singh MM, Paliwal JK, Kamboj VP, Gupta RC. Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of centchroman in rats. Contraception 2002;66:47–56. [62] Ratna S, Roy SK, Ray S, et al. Centchroman: in vitro metabolism by rat liver homogenate. Drug Dev Res 1986;7:173–8. [63] Kole PL, Ray S. Synthesis of trans-2,2-dimethyl-3-phenyl-4-(p-βpyrrolidinoethoxy) phenyl-7-methoxy-(2-12C)chroman. J Labelled Compd Radiopharm 1978;16:373–6. [64] Mishra NC, Ray S, Roy SK. Influence of centchroman on some hepatic microsomal enzymes in female rhesus monkeys. Med Sci Res 1990;18:881–2. [65] Ganong WF. Review of Medical Physiology. California: Lange Medical Publications; 1985. p. 575. [66] Paliwal JK, Grover PK, Asthana OP, Nityanand S, Gupta RC. Excretion of centchroman in breast milk. Br J Clin Pharmacol 1994;38:485–6. [67] Gupta RC, Paliwal JK, Nityanand S, Asthana OP, Lal J. Centchroman: a new nonsteroidal oral contraceptive in human milk. Contraception 1995;52:301–5. [68] Atkinson HC, Begg EJ, Darlow BA. Guide to safety of drugs in human milk. Clinical Pharmacokinetics Drug Data Handbook, 4. Sydney: Adis Press; 1990. p. 125–64. [69] Khurana M, Lal J, Kamboj VP, Nityanand S, Gupta RC. Pharmacokinetic interaction of tetracycline with centchroman in healthy female volunteers. Drugs R D 2003;4:293–9.