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Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs
Citations from the Literature
glucuronide rose with treatment but was indistinguishable in nonsmokers and smokers. However, maximum changes in serum estrone sulfate were greater in smokers after administration of estrogen, suggesting a hepatic effect. Urinary estrone glucuronide levels increased after 8 h of oral estrogen but were similar in nonsmokers and smokers with the two doses. It appears that even moderate smoking, as studied here, induces significant changes in hepatic estrogen metabolism and is best reflected by alterations in serum estrone sulfate and sexhormone-binding-globulin-binding capacity that result in decreased serum unbound estradiol. However, these changes do not appear to require increasing the estrogen dosage to achieve physiologic levels of estrogen in postmenopausal smokers.
ORAL CONTRACEPTION Serum pluumrcokinetics of orally administered desogestrel and binding of contraceptive proges@gens to sex hormoae-binding globulin
Bergink W, Assendorp R; Kloosterbo-er L: Van Lier W: Voortman G; Qvist I Scientific Development Group, Organon International B. V., P.O. Box 20, 5340 BH Oss, NLD
AM J OBSTET GYNECOL 1990 163/6 II SUPPL. (2132-2137) Serum levels of 3-ketodesogestrel and ethinyl estradiol were analyzed by radioimmunoassay in a balanced crossover study with two tablet formulations containing desogestrel (0. I50 mg) and ethinyl estradiol (0.030 mg) in 25 women under steadystate conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: (I) maximum serum concentration. (2) time to maximum serum concentration, (3) total area under the serum concentration versus time curve, and (4) serum half-life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing ethinyl estradiol and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their aflinity to sex hormone-binding globulin and the concentration of sex hormone-binding globulin. We analyzed the structural features that determine binding to sex hormone-binding globulin. The I g-methyl group increased and the I I-methylene group weakened the binding to sex hormonebinding globulin. The double bond at C- I5 reinforced the binding only when combined with an Il-methyl group. Therefore, the binding of Ievonorgestrel (the l&methyl derivative of norethisterone) and gestodene (the Delta-15.18 methyl derivative of norethisterone) to sex hormone-binding globulin was much stronger than that of 3-keto-desogestrel and norethisterone.
259
AM J OBSTET GYNECOL 1991 164/l 1(28-33) Despite the widespread use of tetracycline for treatment of dermatologic disorders and sexually transmitted diseases, the pharmacodynamics of oral contraceptive use in the presence of tetracycline has not been studied. Seven normal women ingested an oral contraceptive containing ethinyl estradiol 35 pg and norethindrone I mg in the follicular phase of the menstrual cycle. On day 0 baseline ethinyl estradiol and norethindrone levels were obtained at 0, I/2, 314, I, 2,4, 12, and 24 h after oral contraceptive administration. On day I tetracycline 500 mg was given orally every 6 h while the oral contraceptive was continued. Tetracycline. ethinyl estradiol, and noethindrone levels were determined at the same time intervals as on day 0. Oral contraceptive and tetracycline were continued for up to IO days, and additional concentrations of ethinyl estradiol, norethindrone, and tetracycline were determined between days 5 and IO. Four additional normal women ingested tetracycline for 5 to 10 days. Tetracycline levels were determined at the time intervals noted above on day I and days 5 to IO. No significant decrease in plasma ethinyl estradiol or norethindrone concentration was seen with either short-term (24 hours) or long-term (5 to IO days) ingestion of tetracycline. Similarly, levels of tetracycline do not significantly decrease with ingestion of a low-dose oral contraceptive. labibition of oral contrawptive steroid-metabolizing enzymes by steroids and drugs
Guengerich FP Department
of Biochemistry,
Medicine, Nashville,
Vanderbilt
University,
School of
TN 37232, USA
AM J OBSTET GYNECOL 1990 l63/6 II SUPPL. (2159-2163) The major l7ol-ethinyl estradiol 2-hydroxylase in humans is the hepatic enzyme cytochrome P-450 IIIA4 (P-450NF). which is known to be inducible by rifampicin or barbiturates. The literature indicates that l7@-estradiol, progesterone, and norgestrel are competitive inhibitors and that primaquine and tolbutamide are rather weak noncompetitive inhibitors. Recent experiments in this laboratory indicate that gestodene is a relatively potent mechanism-based inactivator of cytochrome P-450 IIIA4 in vitro. Inhibition requires incubation with the reduced form of nicotinamide adenine dinucleotide phosphate, is time and concentration dependent, and can be partially blocked by the presence of noninhibitory cytochrome P-450 IIIA4 substrates. The in vitro activation by gestodene provides a possible explanation for the increase in plasma estrogen levels reported in women administered gestodene along with I7cY-ethinyl estradiol. Oral contraception in disease states
Breckwoldt M; Wieacker P; Geisthovel F Division of Clinical Endocrinology, Department of Obstetrics and Gynecology, University of Freiburg, Hugstetterstrasse 55,
The effect of tetracycline on levels of oral contraceptives Murphy AA; Zacur HA; Charache P; Burkman RT
D-7800 Freiburg im Breisgau, DEU AM J OBSTET GYNECOL 1990
UCSD Medical Center, Department of Reproductive Medicine, T-002, 225 W. Dickinson Street, San Diego, CA 92103. USA
(2213-2216) Oral contraceptives are clearly contraindicated
l63/6
II
SUPPL.
in patients
Int J Gynecol Obstet 36
glucuronide rose with treatment but was indistinguishable in nonsmokers and smokers. However, maximum changes in serum estrone sulfate were greater in smokers after administration of estrogen, suggesting a hepatic effect. Urinary estrone glucuronide levels increased after 8 h of oral estrogen but were similar in nonsmokers and smokers with the two doses. It appears that even moderate smoking, as studied here, induces significant changes in hepatic estrogen metabolism and is best reflected by alterations in serum estrone sulfate and sexhormone-binding-globulin-binding capacity that result in decreased serum unbound estradiol. However, these changes do not appear to require increasing the estrogen dosage to achieve physiologic levels of estrogen in postmenopausal smokers.
ORAL CONTRACEPTION Serum pluumrcokinetics of orally administered desogestrel and binding of contraceptive proges@gens to sex hormoae-binding globulin
Bergink W, Assendorp R; Kloosterbo-er L: Van Lier W: Voortman G; Qvist I Scientific Development Group, Organon International B. V., P.O. Box 20, 5340 BH Oss, NLD
AM J OBSTET GYNECOL 1990 163/6 II SUPPL. (2132-2137) Serum levels of 3-ketodesogestrel and ethinyl estradiol were analyzed by radioimmunoassay in a balanced crossover study with two tablet formulations containing desogestrel (0. I50 mg) and ethinyl estradiol (0.030 mg) in 25 women under steadystate conditions after 21 days of treatment. The pharmacokinetic properties of desogestrel were characterized by the following parameters: (I) maximum serum concentration. (2) time to maximum serum concentration, (3) total area under the serum concentration versus time curve, and (4) serum half-life of elimination. The interindividual variation in these parameters was comparable with that observed with other contraceptive combinations containing ethinyl estradiol and norethisterone, levonorgestrel, or gestodene. The serum distribution of contraceptive progestogens is known to be determined by their aflinity to sex hormone-binding globulin and the concentration of sex hormone-binding globulin. We analyzed the structural features that determine binding to sex hormone-binding globulin. The I g-methyl group increased and the I I-methylene group weakened the binding to sex hormonebinding globulin. The double bond at C- I5 reinforced the binding only when combined with an Il-methyl group. Therefore, the binding of Ievonorgestrel (the l&methyl derivative of norethisterone) and gestodene (the Delta-15.18 methyl derivative of norethisterone) to sex hormone-binding globulin was much stronger than that of 3-keto-desogestrel and norethisterone.
259
AM J OBSTET GYNECOL 1991 164/l 1(28-33) Despite the widespread use of tetracycline for treatment of dermatologic disorders and sexually transmitted diseases, the pharmacodynamics of oral contraceptive use in the presence of tetracycline has not been studied. Seven normal women ingested an oral contraceptive containing ethinyl estradiol 35 pg and norethindrone I mg in the follicular phase of the menstrual cycle. On day 0 baseline ethinyl estradiol and norethindrone levels were obtained at 0, I/2, 314, I, 2,4, 12, and 24 h after oral contraceptive administration. On day I tetracycline 500 mg was given orally every 6 h while the oral contraceptive was continued. Tetracycline. ethinyl estradiol, and noethindrone levels were determined at the same time intervals as on day 0. Oral contraceptive and tetracycline were continued for up to IO days, and additional concentrations of ethinyl estradiol, norethindrone, and tetracycline were determined between days 5 and IO. Four additional normal women ingested tetracycline for 5 to 10 days. Tetracycline levels were determined at the time intervals noted above on day I and days 5 to IO. No significant decrease in plasma ethinyl estradiol or norethindrone concentration was seen with either short-term (24 hours) or long-term (5 to IO days) ingestion of tetracycline. Similarly, levels of tetracycline do not significantly decrease with ingestion of a low-dose oral contraceptive. labibition of oral contrawptive steroid-metabolizing enzymes by steroids and drugs
Guengerich FP Department
of Biochemistry,
Medicine, Nashville,
Vanderbilt
University,
School of
TN 37232, USA
AM J OBSTET GYNECOL 1990 l63/6 II SUPPL. (2159-2163) The major l7ol-ethinyl estradiol 2-hydroxylase in humans is the hepatic enzyme cytochrome P-450 IIIA4 (P-450NF). which is known to be inducible by rifampicin or barbiturates. The literature indicates that l7@-estradiol, progesterone, and norgestrel are competitive inhibitors and that primaquine and tolbutamide are rather weak noncompetitive inhibitors. Recent experiments in this laboratory indicate that gestodene is a relatively potent mechanism-based inactivator of cytochrome P-450 IIIA4 in vitro. Inhibition requires incubation with the reduced form of nicotinamide adenine dinucleotide phosphate, is time and concentration dependent, and can be partially blocked by the presence of noninhibitory cytochrome P-450 IIIA4 substrates. The in vitro activation by gestodene provides a possible explanation for the increase in plasma estrogen levels reported in women administered gestodene along with I7cY-ethinyl estradiol. Oral contraception in disease states
Breckwoldt M; Wieacker P; Geisthovel F Division of Clinical Endocrinology, Department of Obstetrics and Gynecology, University of Freiburg, Hugstetterstrasse 55,
The effect of tetracycline on levels of oral contraceptives Murphy AA; Zacur HA; Charache P; Burkman RT
D-7800 Freiburg im Breisgau, DEU AM J OBSTET GYNECOL 1990
UCSD Medical Center, Department of Reproductive Medicine, T-002, 225 W. Dickinson Street, San Diego, CA 92103. USA
(2213-2216) Oral contraceptives are clearly contraindicated
l63/6
II
SUPPL.
in patients
Int J Gynecol Obstet 36