- Email: [email protected]
230. Pharmacodynamic effects of the norethisterone minipill
Abstracts
860
there wcrc 4 women who received 100 mg of norethisterone oenanthatc intra-muscularly while group III was composed of 4 women who received I50 mg of medroxyprogesterone acctatc intra-muscularly on the fifth day of the cycle. In the latter two groups. besides premenstrual endometrial biopsies in the control cycle. rurther biopsies were done three and live months post injection. Dating of the endomctrium was ditlicult due to disparity between the glandular. stromal and vascular components. However. in group III all biopsies showed non-secretory endometrium.
these women in the levels of total lipids. esterified terol. triglycerides and a and b-lipoproteins.
choles-
228. Coagulation
type of
studies in women on combination
oral contraceptives
GUPTA. K.. NAIK. S.. RAJWADE. N.. SHETH. U. K.. *VAIDYA. P.. *MANDLEKAR, A. and *KRISHNA. U.. Department of Pharmacology and Clinical Pharmacology Unit. Seth G. S. Medical College and K.E.M. Hospital. Bombay-II; and *Department of Gynaecology and Obstetrics. K.E.M. Hospital. Bombay-12
225. Plasma levels of norethindrone
in Indian women who received norethindrone enanthate injectable PWASAV. K. V. S.. PREMA. K.. MADHAVAN NAIR. K.
and NAKASINGA RAO. B. S.. National Nutrition. Hyderabad-SIOOO7. India
Institute
of
In relation to our studies on the effects of malnutrition OII the bioavailability of contraceptive drugs. six apparcntly normal women of varying socio-economic status were investigated using injectable norethindrone enanthate (NE). Each subject received 10mg NE intramuscularly on day 5 of the cycle and blood was collected twice weekly fcjr the next one month. Plasma levels of norethindrone and progesterone (marker of ovulation) were estimated by radioimmunoassay. Evidence will be presented for suggesting that the rate of clearance of the drug from the plasma is related to the nutritional SIRIUS of the individual.
226. Pharmacokinetics
of norethindrone from oral pills in Indian women in relation to their nutritional status
PRASAD. K. V. S.. NARASINGA RAO. B. S.. SIVAKUMAR. B. and PREMA. K.. National Institute of Nutrition. Hyderabad-500007. India The objective of this study was to determine the pharmacokinetics of a contraceptive steroid drug. norethindrone (NET). in Indian women in relation to their nutritional status. An oral dose of 0.35 mg NET was given to seventeen apparently healthy women of reproductive age drawn from different socio-economic strata and with varying indices of anthropometry. Pharmacokinetics of NET was studied in these women by estimating the NET levels in plasma by radioimmunoassay. Absorption of the drug was rapid and the drug elimination curve was round to be biphasic. The f, &I) and I, *(fl) of the two phases were shorter as compared to the values reported in the Western women. Besides. there appears to be a relationship between I, z(/Y)on one hand and the nutritional status of the subject as reflected by the unthropometry. on the other.
227. Serum lipid studies in women using combination
type
of oral contraceptives
VAIDYA. P.. KRISHNA. U.. GUPTA. K.. NAIK. S.. MANIICERI. S. and SHETH. U. K.. Department of Gynaecology and Obstetrics. K.E.M. Hospital. Bombay and Department of Pharmacology and Clinical Pharmacology Unit. Seth G. S. Medical College and K.E.M. Hospital. Bombay-l? Oral contraceptives are known to produce changes in various metabolic processes. lipid metabolism being one or them. We have studied lipid metabolism in women on combination type of oral contraceptives. Serum lipids of 15 women on oral contraceptives for less than 5 years and 39 women on oral contraceptives for more than 5 years were compared with each other and also with a control group of 22 women. in whom basal readings were obtained before starting the study. A significant rise in total serum cholesterol and free cholesterol was noticed in women on oral contraceptives. No significant change was seen in
Combination type of oral contraceptives have been implicated as causative agents of thromboembolic episodes. In the present study we have studied some parameters of coagulation of women on oral contraceptives. Twenty five women before starting oral contraceptives, I6 on oral contraceptives for I&S years and 35 cases on oral contraceptives for 5 or more years, were studied for prothrombin time. partial thromboplastin time, thrombin time, euglobulin clot lysis time. platelet count. platelet adhesiveness and platelet aggregation. Statistically significant changes were found in partial thrombo plastin time. platelet count. and platelet aggregation.
229. Effect of a single silastic implant
containing
norethin-
drone acetate on human lactation
JAMWAL. K..* YADA~. H. S.,t AGARWAL, N.* and of Obstetrics and HINGORANI. V.,* Departments *Gynaecology and tReproductive Biology. India lnstitute of Medical Sciences, New Delhi, India The effect of a single silastic implant containing 40mg of norethindrone acetate on the quantity and quality of milk in 10 normally lactating women was studied. Implant insertion was carried out 6 weeks after delivery. These results are compared with 10 healthy lactating women using conventional methods of contraception who served as a control group. The results show that the quantity of milk is not altered within 2-3 months of implant insertion. However. after 3-4 months of use the quantity of milk is significantly reduced. The quality of milk did not show any appreciable changes except slight decrease in milk protein content after 3-4 months of use. Other clinical observations including the baby’s weight, arm circumference and skinfold thickness did not show any change with the use of this implant.
230. Pharmacodynamic effects of the norethisterone minipill LANDGREN. B.-M. and DICZFALUSY. E.. Swedish Medical Research Council. Reproductive Endocrinology Research Unit and Department of Obstetrin and Gynaecology. Karolinska Sjukhuset. 104 01 Stockholm 60. Sweden The pharmacodynamic effects of the daily administration of 3OOpg of norethisterone were studied in 43 women by analysing the day-to-day changes in the plasma levels of estradiol. progesterone. FSH and both bioactive and immunoactive LH during a control cycle (without treatment) and during the second consecutive treatment cycle. In 21 of the subjects hormone assays were also carried out during the sixth consecutive treatment cycle and the daily plasma levels of 17-hydroxyprogesterone and 2@z_dihydroprogesterone were also analysed during the entire study. Our previous study of the daily hormone levels in 106 normally menstruating women revealed that 94”, of normal ovulatory cycles exhibit plasma progesterone levels above 5.0 ng,ml for at least 5 days. Using this criterion. some 40”” of the treatment cycles were ovulatory, 40”,, were without any luteal activity and IO”, showed insuffi-
861
Abslracts cicnt luteal function. In several subjects the admintstration of the minipill completely abolished or drastically reduced the midcycle surge of LH and FSH. without any apparent effect on the normal “ovulatory” pattern of plasma progesterone and oestradiol levels. It is concluded that the administration the minipill disrupts the normal pituttary-ovarian regulatory mechantsms. wtthout necessarily inht-
of
bttmg ovulatton.
8bsorption of [‘HI-oorcthiodrooe pelkts in r8ls rod r&bits
23l.Stxstaimd
absorb8Mc
from
bio-
G. N.. The Population Counctl. The Rockefeller Universtty. New York. NY 10021. U.S.A.
determine and compare continuation ol DMPA.
the tnferttle intervals between disIUD’s. oral pills. and no-contra-
ception pts. and the establishment
of subsequent
pregnan-
cies. The ultimate pregnancy rate was similar in all groups with a moderate prolongation ol the free interval [or DM PA. It IS concluded that prolonged use of DM PA contraceptive injections does not in itself pose a threat to the establishment of a subsequent pregnancy and that the return of lertiltty after discontinuatton IS stmilar to that seen after the use of oral pills. IUD’s. and no-contracept ion.
&PTA.
Bto-absorbable pellets (size 5.4 x 3.1 x 2.6mm: 30mg mass) comprrsing 95”,, [‘HI-Norethindrone ([‘HI-NET) plus Is”,, cholesterol with a high specific activity of T’Hl-NET were oreoared. The 3-month release rates of [‘Hj-NET from these pellets have been observed in WI rirro and tn riro studies. The average release rate. in rirro. over a perrod of 90 days ts 38 t 4pg/day per pellet. after initial 5 days ol high release. The absorption studies of [‘HI-NET tn groups of rats and rabbits over a 2-month period have been completed. The daily absorption rates of [‘HI-NET based on dally urutary and fecal excretion of radtoacttvny over a ‘-month period are 6&75pg/day per pellet m the rat and 78-l 13pg;day per pellet in the rabbtt. The correlation of the excretory values with plasma progestin levels will be presented. 232. !Mine-lWed
delivery
sil8stic crpla: system for intn-utcrim
8
more surtrined contnception
steroid
DILEEPKUMAR. S. A.. FARWQ. A. and LAUMAS. K. R.. Department of Reproductive Biology. All lndta Instttute of Medical Sctences. New Delhi-l 10016. lndta A silasttc capsule (rd. 1.57mm. o.d. 3.18mmt containing 7.9 mg of crystalline norethmdrone acetate packed up to 5 mm length. release in r11ro 50 pg/day nutially The release decreased steadily to 25pg,day on day 12. Thereafter tt gradually decreased IO as low as 6.8pglday on day 210. In a modified design. a rod shaped pellet (dia. 1.47mm. length 4 mm) of the same amount oC the steroid was placed mside the silasttc capsule of the same dimensions and the extra space around the pellet was filled with phystological sahne. The pattern of sterotd released from the saline filled system was altogether different as the inntal release was only 28 rg day which gradually decreased to I7 pg,day on day 17. and IS 5rg:day on day 210 It IS evident from the above that the diffusion ol the steroid through stlasttc capsules decreases exponenttally with ttme The incorporatton of fluid rsalnte) m the system not only caused a marked decrease m the mctial release but also a much more sustained release As a uniform therapeutic regime is the prerequistte for intra-uterine contraception. it may be concluded that. since the tluid-filled system definitely provides a more sustained release. it may thereby prove to be more effective for Intrauterine sterotd delivery.
233. Return
acet8te
of fertility rfter depot medroxyprogesterone DIMPA contrrccptive injectioos
MCDANIEL. E. B. and PRADTHAISONC, T..* MaCormick Hospital, Chiang Mai. Thailand, and *Department of Preventive and Social Medicine. Faculty ol Medicine. Chiang Mai University. Chiang Mat. Thatland In order to study whether long-term use ofdepot medroxyprogesterone acetate (DMPA) contracepttve injections tnduced sterility or prolonged infertility in women dtscontinuing the method for planned pregnancy. a large, longterm. retrospective rapprox. 500 DMPA subjects) and prospective (470 DMPA subjects) study was performed to
23.4. Etfect of noretbiodrone
aceI8te alone or in combin8tion with testostcrooe 00 histology of the testis and plasma testosterone kvek in 1-81s BANDOPADHYAYA. G P.. DILEEPKUMAR. S. A.. RAHMAN. A., FAROOQ. M. M. and KAPUR. Department of Reproductive Biology and Department of Surgery. All India Institute of Medical Sciences. New DelhiIlOOl6, India
Several
progestational
compounds.
through
different
routes. have been tried for suppression of rcrttlity In males. The higher doses used earlier were round to be associated with loss of libido. potency and onset of gynecomastia. Attempts were therelore made to suppress spermatogenests wtth mtcroquanttties of norethindrone acetate NETA while maintaining libtdo and potency by testosterone released through silastic implants. An implant of NETA releasing approximately 306pg;24 h produced a stgntficant lall m plasma testosterone levels with the suppresston of spermatogenesis. as only spermatogonia and sertoli cells were seen. The addition of testosterone implants releasmg 45pgi24 h maintained the plasma testosterone levels and spermatogenesis. However. loo”,. stertltty was produced tn all antmal groups administered with NETA alone or tn combinatton with testosterone.
235. Metabolic clerrnnce r8te of norethindrone acetate in women before rod 8ffer tbe imcrtion of steroid relnsing impl8nf SINCH. H.. UNIYAL, J. P.. JHA. P.. TAKKAR. D. and MURUGESAN. K.. Departments of Reproducttve Biology and Obstetrics and Gynaecology. All lndta Institute of Medtcal Sciences. New Delhi-l 10016. India Plasma half-life and metabolic clearance rate (MCR) of norethindrone acetate was determmcd after a stngle tntravenous injection to women. Norethmdrone acetate gets rapidly metaboltsed ntto norethmdrone alter the intravenous inJection. As early as 5mtn after the mjectton. 0.739, of the inJected dose was detected as norethmdrone while the parent sterotd accounted for only 0.4l’i,, of the injected dose. Norethindrone acetate follows a btohastc pattern of disappearance m plasma with an initial half-lire or 7.5 min followed by a slower dtsappearance wtth a halfltfe of 5.1 + 2.2 h. The metaboltc clearance rate or norethmdrone acetate was round to be 495 + 74 I;day Norethmdrone. the major metabolite of norethmdrone acetate. dtsappeared from the plasma with a half-life ol 34.8 + 3.5 h. The effect of long-term treatment with norethindrone acetate-releasing Implant on the metabolic clearance rate or norethtndrone acetate was studied tn three uomen. It was observed that during the first week and first month ol the implant insertion the MCR showed a slight decrease while at 2 months the value of MCR approached the normal value 1445 I:day). In the sixth cycle after the Implant insertion the MCR showed an Increase above the control value to 711 l/day. Supported by grant to Professors K. Laumas and V. Hingorani.
860
there wcrc 4 women who received 100 mg of norethisterone oenanthatc intra-muscularly while group III was composed of 4 women who received I50 mg of medroxyprogesterone acctatc intra-muscularly on the fifth day of the cycle. In the latter two groups. besides premenstrual endometrial biopsies in the control cycle. rurther biopsies were done three and live months post injection. Dating of the endomctrium was ditlicult due to disparity between the glandular. stromal and vascular components. However. in group III all biopsies showed non-secretory endometrium.
these women in the levels of total lipids. esterified terol. triglycerides and a and b-lipoproteins.
choles-
228. Coagulation
type of
studies in women on combination
oral contraceptives
GUPTA. K.. NAIK. S.. RAJWADE. N.. SHETH. U. K.. *VAIDYA. P.. *MANDLEKAR, A. and *KRISHNA. U.. Department of Pharmacology and Clinical Pharmacology Unit. Seth G. S. Medical College and K.E.M. Hospital. Bombay-II; and *Department of Gynaecology and Obstetrics. K.E.M. Hospital. Bombay-12
225. Plasma levels of norethindrone
in Indian women who received norethindrone enanthate injectable PWASAV. K. V. S.. PREMA. K.. MADHAVAN NAIR. K.
and NAKASINGA RAO. B. S.. National Nutrition. Hyderabad-SIOOO7. India
Institute
of
In relation to our studies on the effects of malnutrition OII the bioavailability of contraceptive drugs. six apparcntly normal women of varying socio-economic status were investigated using injectable norethindrone enanthate (NE). Each subject received 10mg NE intramuscularly on day 5 of the cycle and blood was collected twice weekly fcjr the next one month. Plasma levels of norethindrone and progesterone (marker of ovulation) were estimated by radioimmunoassay. Evidence will be presented for suggesting that the rate of clearance of the drug from the plasma is related to the nutritional SIRIUS of the individual.
226. Pharmacokinetics
of norethindrone from oral pills in Indian women in relation to their nutritional status
PRASAD. K. V. S.. NARASINGA RAO. B. S.. SIVAKUMAR. B. and PREMA. K.. National Institute of Nutrition. Hyderabad-500007. India The objective of this study was to determine the pharmacokinetics of a contraceptive steroid drug. norethindrone (NET). in Indian women in relation to their nutritional status. An oral dose of 0.35 mg NET was given to seventeen apparently healthy women of reproductive age drawn from different socio-economic strata and with varying indices of anthropometry. Pharmacokinetics of NET was studied in these women by estimating the NET levels in plasma by radioimmunoassay. Absorption of the drug was rapid and the drug elimination curve was round to be biphasic. The f, &I) and I, *(fl) of the two phases were shorter as compared to the values reported in the Western women. Besides. there appears to be a relationship between I, z(/Y)on one hand and the nutritional status of the subject as reflected by the unthropometry. on the other.
227. Serum lipid studies in women using combination
type
of oral contraceptives
VAIDYA. P.. KRISHNA. U.. GUPTA. K.. NAIK. S.. MANIICERI. S. and SHETH. U. K.. Department of Gynaecology and Obstetrics. K.E.M. Hospital. Bombay and Department of Pharmacology and Clinical Pharmacology Unit. Seth G. S. Medical College and K.E.M. Hospital. Bombay-l? Oral contraceptives are known to produce changes in various metabolic processes. lipid metabolism being one or them. We have studied lipid metabolism in women on combination type of oral contraceptives. Serum lipids of 15 women on oral contraceptives for less than 5 years and 39 women on oral contraceptives for more than 5 years were compared with each other and also with a control group of 22 women. in whom basal readings were obtained before starting the study. A significant rise in total serum cholesterol and free cholesterol was noticed in women on oral contraceptives. No significant change was seen in
Combination type of oral contraceptives have been implicated as causative agents of thromboembolic episodes. In the present study we have studied some parameters of coagulation of women on oral contraceptives. Twenty five women before starting oral contraceptives, I6 on oral contraceptives for I&S years and 35 cases on oral contraceptives for 5 or more years, were studied for prothrombin time. partial thromboplastin time, thrombin time, euglobulin clot lysis time. platelet count. platelet adhesiveness and platelet aggregation. Statistically significant changes were found in partial thrombo plastin time. platelet count. and platelet aggregation.
229. Effect of a single silastic implant
containing
norethin-
drone acetate on human lactation
JAMWAL. K..* YADA~. H. S.,t AGARWAL, N.* and of Obstetrics and HINGORANI. V.,* Departments *Gynaecology and tReproductive Biology. India lnstitute of Medical Sciences, New Delhi, India The effect of a single silastic implant containing 40mg of norethindrone acetate on the quantity and quality of milk in 10 normally lactating women was studied. Implant insertion was carried out 6 weeks after delivery. These results are compared with 10 healthy lactating women using conventional methods of contraception who served as a control group. The results show that the quantity of milk is not altered within 2-3 months of implant insertion. However. after 3-4 months of use the quantity of milk is significantly reduced. The quality of milk did not show any appreciable changes except slight decrease in milk protein content after 3-4 months of use. Other clinical observations including the baby’s weight, arm circumference and skinfold thickness did not show any change with the use of this implant.
230. Pharmacodynamic effects of the norethisterone minipill LANDGREN. B.-M. and DICZFALUSY. E.. Swedish Medical Research Council. Reproductive Endocrinology Research Unit and Department of Obstetrin and Gynaecology. Karolinska Sjukhuset. 104 01 Stockholm 60. Sweden The pharmacodynamic effects of the daily administration of 3OOpg of norethisterone were studied in 43 women by analysing the day-to-day changes in the plasma levels of estradiol. progesterone. FSH and both bioactive and immunoactive LH during a control cycle (without treatment) and during the second consecutive treatment cycle. In 21 of the subjects hormone assays were also carried out during the sixth consecutive treatment cycle and the daily plasma levels of 17-hydroxyprogesterone and 2@z_dihydroprogesterone were also analysed during the entire study. Our previous study of the daily hormone levels in 106 normally menstruating women revealed that 94”, of normal ovulatory cycles exhibit plasma progesterone levels above 5.0 ng,ml for at least 5 days. Using this criterion. some 40”” of the treatment cycles were ovulatory, 40”,, were without any luteal activity and IO”, showed insuffi-
861
Abslracts cicnt luteal function. In several subjects the admintstration of the minipill completely abolished or drastically reduced the midcycle surge of LH and FSH. without any apparent effect on the normal “ovulatory” pattern of plasma progesterone and oestradiol levels. It is concluded that the administration the minipill disrupts the normal pituttary-ovarian regulatory mechantsms. wtthout necessarily inht-
of
bttmg ovulatton.
8bsorption of [‘HI-oorcthiodrooe pelkts in r8ls rod r&bits
23l.Stxstaimd
absorb8Mc
from
bio-
G. N.. The Population Counctl. The Rockefeller Universtty. New York. NY 10021. U.S.A.
determine and compare continuation ol DMPA.
the tnferttle intervals between disIUD’s. oral pills. and no-contra-
ception pts. and the establishment
of subsequent
pregnan-
cies. The ultimate pregnancy rate was similar in all groups with a moderate prolongation ol the free interval [or DM PA. It IS concluded that prolonged use of DM PA contraceptive injections does not in itself pose a threat to the establishment of a subsequent pregnancy and that the return of lertiltty after discontinuatton IS stmilar to that seen after the use of oral pills. IUD’s. and no-contracept ion.
&PTA.
Bto-absorbable pellets (size 5.4 x 3.1 x 2.6mm: 30mg mass) comprrsing 95”,, [‘HI-Norethindrone ([‘HI-NET) plus Is”,, cholesterol with a high specific activity of T’Hl-NET were oreoared. The 3-month release rates of [‘Hj-NET from these pellets have been observed in WI rirro and tn riro studies. The average release rate. in rirro. over a perrod of 90 days ts 38 t 4pg/day per pellet. after initial 5 days ol high release. The absorption studies of [‘HI-NET tn groups of rats and rabbits over a 2-month period have been completed. The daily absorption rates of [‘HI-NET based on dally urutary and fecal excretion of radtoacttvny over a ‘-month period are 6&75pg/day per pellet m the rat and 78-l 13pg;day per pellet in the rabbtt. The correlation of the excretory values with plasma progestin levels will be presented. 232. !Mine-lWed
delivery
sil8stic crpla: system for intn-utcrim
8
more surtrined contnception
steroid
DILEEPKUMAR. S. A.. FARWQ. A. and LAUMAS. K. R.. Department of Reproductive Biology. All lndta Instttute of Medical Sctences. New Delhi-l 10016. lndta A silasttc capsule (rd. 1.57mm. o.d. 3.18mmt containing 7.9 mg of crystalline norethmdrone acetate packed up to 5 mm length. release in r11ro 50 pg/day nutially The release decreased steadily to 25pg,day on day 12. Thereafter tt gradually decreased IO as low as 6.8pglday on day 210. In a modified design. a rod shaped pellet (dia. 1.47mm. length 4 mm) of the same amount oC the steroid was placed mside the silasttc capsule of the same dimensions and the extra space around the pellet was filled with phystological sahne. The pattern of sterotd released from the saline filled system was altogether different as the inntal release was only 28 rg day which gradually decreased to I7 pg,day on day 17. and IS 5rg:day on day 210 It IS evident from the above that the diffusion ol the steroid through stlasttc capsules decreases exponenttally with ttme The incorporatton of fluid rsalnte) m the system not only caused a marked decrease m the mctial release but also a much more sustained release As a uniform therapeutic regime is the prerequistte for intra-uterine contraception. it may be concluded that. since the tluid-filled system definitely provides a more sustained release. it may thereby prove to be more effective for Intrauterine sterotd delivery.
233. Return
acet8te
of fertility rfter depot medroxyprogesterone DIMPA contrrccptive injectioos
MCDANIEL. E. B. and PRADTHAISONC, T..* MaCormick Hospital, Chiang Mai. Thailand, and *Department of Preventive and Social Medicine. Faculty ol Medicine. Chiang Mai University. Chiang Mat. Thatland In order to study whether long-term use ofdepot medroxyprogesterone acetate (DMPA) contracepttve injections tnduced sterility or prolonged infertility in women dtscontinuing the method for planned pregnancy. a large, longterm. retrospective rapprox. 500 DMPA subjects) and prospective (470 DMPA subjects) study was performed to
23.4. Etfect of noretbiodrone
aceI8te alone or in combin8tion with testostcrooe 00 histology of the testis and plasma testosterone kvek in 1-81s BANDOPADHYAYA. G P.. DILEEPKUMAR. S. A.. RAHMAN. A., FAROOQ. M. M. and KAPUR. Department of Reproductive Biology and Department of Surgery. All India Institute of Medical Sciences. New DelhiIlOOl6, India
Several
progestational
compounds.
through
different
routes. have been tried for suppression of rcrttlity In males. The higher doses used earlier were round to be associated with loss of libido. potency and onset of gynecomastia. Attempts were therelore made to suppress spermatogenests wtth mtcroquanttties of norethindrone acetate NETA while maintaining libtdo and potency by testosterone released through silastic implants. An implant of NETA releasing approximately 306pg;24 h produced a stgntficant lall m plasma testosterone levels with the suppresston of spermatogenesis. as only spermatogonia and sertoli cells were seen. The addition of testosterone implants releasmg 45pgi24 h maintained the plasma testosterone levels and spermatogenesis. However. loo”,. stertltty was produced tn all antmal groups administered with NETA alone or tn combinatton with testosterone.
235. Metabolic clerrnnce r8te of norethindrone acetate in women before rod 8ffer tbe imcrtion of steroid relnsing impl8nf SINCH. H.. UNIYAL, J. P.. JHA. P.. TAKKAR. D. and MURUGESAN. K.. Departments of Reproducttve Biology and Obstetrics and Gynaecology. All lndta Institute of Medtcal Sciences. New Delhi-l 10016. India Plasma half-life and metabolic clearance rate (MCR) of norethindrone acetate was determmcd after a stngle tntravenous injection to women. Norethmdrone acetate gets rapidly metaboltsed ntto norethmdrone alter the intravenous inJection. As early as 5mtn after the mjectton. 0.739, of the inJected dose was detected as norethmdrone while the parent sterotd accounted for only 0.4l’i,, of the injected dose. Norethindrone acetate follows a btohastc pattern of disappearance m plasma with an initial half-lire or 7.5 min followed by a slower dtsappearance wtth a halfltfe of 5.1 + 2.2 h. The metaboltc clearance rate or norethmdrone acetate was round to be 495 + 74 I;day Norethmdrone. the major metabolite of norethmdrone acetate. dtsappeared from the plasma with a half-life ol 34.8 + 3.5 h. The effect of long-term treatment with norethindrone acetate-releasing Implant on the metabolic clearance rate or norethtndrone acetate was studied tn three uomen. It was observed that during the first week and first month ol the implant insertion the MCR showed a slight decrease while at 2 months the value of MCR approached the normal value 1445 I:day). In the sixth cycle after the Implant insertion the MCR showed an Increase above the control value to 711 l/day. Supported by grant to Professors K. Laumas and V. Hingorani.