Intraindividual comparison of pharmacokinetic parameters of d-norgestrel, lynestrenol and cyproterone acetate in 6 women

Hümpel, M.; Wendt, H.; Dogs, G.; Weiβ, Chr.; Rietz, Stephan; Speck, Ulrich

doi:10.1016/0010-7824(77)90087-7

Cited by 38 publications

(7 citation statements)

References 25 publications

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“…Pharmacokinetic parameters of LNG determined on day 21 of treatment were in good agreement with those reported recently in a study including 8 Japanese women who received the same triphasic preparation over one treatment cycle [5], Since in both studies, terminal halflife determination of LNG was based on concentration values determined up to 48 h postadministration, the half-life values of approximately 22 h (former study) or 28 h in the present study were about twice as high as corresponding values based on LNG concentrations, de termined only up to 24 h after drug intake [2][3][4], but in keeping with another study [7], where LNG levels were followed up to 72 h postadministration.…”

Section: Discussionsupporting

confidence: 77%

“…The antiserum (Schering) was obtained by immunization o f rabbits with the immunogen LNG-3-(0-carboxymethyI)-oxime-BSA, the dilution was 1:50,000 in the assay. Plasma samples were extracted with diethylether and the extracts were submitted to radioimmunological analysis analogous with published pocedures [7]. The lower limit o f quantitation was 50pg/ml.…”

Section: Analytical Determinationsmentioning

confidence: 99%

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Pharmacokinetics of Levonorgestrel in 18 Women after 1 Month of Treatment with a Triphasic Oral Contraceptive

Kuhnz¹,

Al-Yacoub²

1991

Horm Res

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A triphasic levonorgestrel (LNG)- and ethinylestradiol-containing oral contraceptive was administered to 18 women. Plasma samples were obtained throughout a treatment cycle just before drug administration and on the last treatment day (day 21), several plasma samples were collected from each individual up to 48 h postadministration. LNG was determined by radioimmunoassay in all plasma samples. In addition, the concentration of sex-hormone-binding globulin (SHBG) was determined in plasma samples collected from the same subjects during treatment, as well as during a pre- and a posttreatment cycle. During the treatment cycle, plasma levels of LNG determined just before drug administration increased and reached steady state at about day 16. This increase was due to an increased dose of LNG according to the triphasic dose regimen, a concomitantly ethinylestradiol-induced increase in SHBG and due to pharmacokinetic accumulation, since LNG had a terminal half-life of approximately 28.5 h and the dosing interval was 24 h. Steady-state levels and pharmacokinetic parameters of LNG determined on the last day of treatment were in good accordance with previously published results.

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Section: Discussionsupporting

confidence: 77%

Section: Analytical Determinationsmentioning

confidence: 99%

Pharmacokinetics of Levonorgestrel in 18 Women after 1 Month of Treatment with a Triphasic Oral Contraceptive

Kuhnz¹,

Al-Yacoub²

1991

Horm Res

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“…This difference in half life between the two gestagens seems to have no clinical importance when low doses are used, since the NET concentrations in plasma after the lower doses of both lyn and NET were very low after 24 h and hardly detectable after 36 h. When higher doses are used the longer half life of lyn may give rise t o an accumulation. After administration of 2.5 mg lynestrenol and 50 pg ethnyloestradiol Humpel et al calculated the half life of radioimmunoassayable NET t o be 3-4 h during the first 12 h and 16.5 h during the period 2 4 t o 7 2 h (Humpel et al, 1977). These authors also showed that after a single oral dose of 2.5 mg ''C-lynestrenol together with 50 pg ethinyloestradiol, lynestrenol or its metabolites, recognized as plasma radioactivity, was detectable t o a considerable degree after 1 2 0 h, indicating an accumulation of the drug or its metabolites.…”

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Norethindrone After Single Oral Dose Administration of Norethindrone and Lynestrenol

Odlind¹,

Weiner²,

Victor³

et al. 1979

Clinical Endocrinology

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Single oral doses of 0.3 mg, 0.5 mg and 5 mg Norethindrone (NET) and 0.5 mg and 5 mg Lynestrenol (lyn) were given to five women. Lynestrenol is probably metabolized through NET and exerts its main biological activity as NET. Plasma concentrations of NET were determined by a radioimmunoassay at different intervals after administration of the tablets. Peak concentrations of NET were found within two hours after intake of each table. The plasma half life of Net after NET and lyn administration for the period 8-24 h was 8-11 h. No significant difference was found between the half life of NET and the NET tablets and after the lyn tablets. When 5 mg NET was given the plasma half life of NET for the period 24-72 h was around 10 h and this was significantly shorter than the half-life of NET after 5 mg lyn, which was 16 1/2 h. The systemic availability of the drugs was estimated by calculating and comparing the areas under the plasma concentration versus time curve (AUC). 0-24 H. The AUC 0.24 after 0.3 MG NET was almost identical to the AUC 0.24 after 0.5 mg lyn. The AUC 0-24 after 0.5 mg NET was significantly larger than after 0.5 lyn. No difference was found between the AUC 0-24 after 5 mg lyn and 5 mg NET. This study supports the concept of a conversion from lyn to NET. It also shows that there were only minor pharmacokinetic differences between the drugs when all samples were measured as NET.

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“…Victor et al (1975) described a radioimmunoassay for lev onorgestrel using antiserum developed against norethisterone. Radioimmunoassays have since been described by Back et al (1981a), Hiimpel et al (1977), Kundu et al (1977). Radioimmunoassays have since been described by Back et al (1981a), Hiimpel et al (1977), Kundu et al (1977).…”

Section: Levonorgestrelmentioning

confidence: 99%

Clinical Pharmacokinetics of Oral Contraceptive Steroids

Orme

Back

Breckenridge

1983

Clinical Pharmacokinetics

159

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Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All. the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone.The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The Ii-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 Llkg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/m!. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 nglml for norethisterone and 0.8 to 4.5 nglml for levonorgestrel.All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin.Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug.

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Intraindividual comparison of pharmacokinetic parameters of d-norgestrel, lynestrenol and cyproterone acetate in 6 women

Cited by 38 publications

References 25 publications

Pharmacokinetics of Levonorgestrel in 18 Women after 1 Month of Treatment with a Triphasic Oral Contraceptive

Pharmacokinetics of Levonorgestrel in 18 Women after 1 Month of Treatment with a Triphasic Oral Contraceptive

Plasma Levels of Norethindrone After Single Oral Dose Administration of Norethindrone and Lynestrenol

Clinical Pharmacokinetics of Oral Contraceptive Steroids

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