Bioavailability of norethindrone in human subjects

Okerholm, Richard A.; Peterson, Floyd E.; Keeley, F.J.; Smith, Thomas C.; Glazko, Anthony J.

doi:10.1007/bf00606680

Cited by 12 publications

(8 citation statements)

References 14 publications

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“…A competitive protein binding assay has been described by Okerholm et al (1978). A competitive protein binding assay has been described by Okerholm et al (1978).…”

Section: Norethisterone (Norethindrone)mentioning

confidence: 99%

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Clinical Pharmacokinetics of Oral Contraceptive Steroids

Orme

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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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“…A competitive protein binding assay has been described by Okerholm et al (1978). A competitive protein binding assay has been described by Okerholm et al (1978).…”

Section: Norethisterone (Norethindrone)mentioning

confidence: 99%

“…Okerholm et al (1978) have compared the plasma concentrations of norethisterone after 2 different preparations of the drug. Okerholm et al (1978) have compared the plasma concentrations of norethisterone after 2 different preparations of the drug.…”

Section: Norethisteronementioning

confidence: 99%

Clinical Pharmacokinetics of Oral Contraceptive Steroids

Orme

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Breckenridge

1983

Clinical Pharmacokinetics

159

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“…According to the previous report, 4) the main metabolic pathway of gemfibrozil in humans was the oxidation of the 5῎-methyl group, yielding a hydroxymethyl group, which was further oxidized to a carboxylic acid. Another pathway included the oxidation of the 4῎-C of the aromatic ring to a phenol.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, these phase I metabolites as well as the unchanged gemfibrozil undergo phase II metabolism mostly by glucuronidation, and are excreted into the urine as the major route of elimination. 4) In vitro, we have found that gemfibrozil is oxidized by human liver microsomes at more than one positions producing a mixture of hydroxylated-form metabolites. These metabolites had the same molecular weight of 266 and were positional isomers with regard to the hydroxyl group.…”

Section: )mentioning

confidence: 97%

“…4)῍7) Phase I oxidation has been reported to occur at three di#erent positions in the 2῏,5῏-dimethylphenoxy moiety, namely at 4῏-C position of the aromatic ring and at the 2῏-methyl and 5῏-methyl groups, leading to a production of carboxylic acid-form metabolites and hydroxylated-form metabolites. In humans, these phase I metabolites as well as the unchanged gemfibrozil undergo phase II metabolism mostly by glucuronidation, and are excreted into the urine as the major route of elimination.…”

Section: )mentioning

confidence: 99%

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Identification of Gemfibrozil Metabolites, Produced as Positional Isomers in Human Liver Microsomes, by On-line Analyses Using Liquid Chromatography/Mass Spectrometry and Liquid Chromatography/Nuclear Magnetic Resonance Spectroscopy

Murai

Iwabuchi

Ikeda

2004

J. Mass Spectrom. Soc. Jpn.

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Liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/nuclear magnetic resonance spectroscopy (LC/NMR) were applied to the identification of the positional isomers of gemfibrozil metabolites produced in vitro by human liver microsomes. Gemfibrozil was metabolized to two major oxidative metabolites (M1 and M2) by human liver microsomes in the presence of an nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-generating system. M1 and M2 were characterized as metabolites formed by the oxidation of the 2῏,5῏-dimethylphenoxy moiety, which has potentially 5 di#erent positions for hydroxylation, based on the results of negative-ion tandem mass spectrometry in combination with those of accurate mass measurements by quadrupole time-of-flight mass spectrometry. Separation and identification of M1 and M2 were conducted by LC/NMR analyses at 500 MHz. An on-flow 1 H NMR analysis demonstrated that M1 was produced by hydroxylation at either the 2῏-methyl group or the 5῏-methyl group and M2 by hydroxylation at either the 3῏-C or the 4῏-C position of the aromatic ring. A stop-flow nuclear Overhauser e#ect spectroscopy (NOESY) analysis demonstrated that M1 and M2 were metabolites hydroxylated at the 5῏-methyl group and the 4῏-C position of the aromatic ring, respectively.

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Kinetics of norethindrone in women; II. Single‐dose kinetics

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Breckenridge

Crawford

et al. 1978

Clin Pharma and Therapeutics

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In order to study the kinetics of norethindrone in women, we have administered single doses of 4 preparations of norethindrone (N) to Liverpool, England Department of Pharmacology and Therapeutics, University of LiverpoolNorethindrone ( 17a -ethinyl-I7 (3 -hydroxyestr-4-en-3-one) is a synthetic progestogen which is widely used both on its own and as a component of many combined contraceptive steroid preparations. Despite its widespread use, little is known of the relationship of blood concentrations of norethindrone to efficacy or toxicity. The plasma half-life (tV2) of norethindrone has been variously estimated as between 3 and 5 hrll and about 6 hr 9 , or as a biexponential decay with a terminal tV2 ranging between 3 and 12 hr. 6 We have developed a sensitive radioimmunoassay method for the measurement of norethindrone concentrations in plasma. 2During our initial studies in women taking the combined form of oral contraceptive, we found

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Bioavailability of norethindrone in human subjects

Cited by 12 publications

References 14 publications

Clinical Pharmacokinetics of Oral Contraceptive Steroids

Clinical Pharmacokinetics of Oral Contraceptive Steroids

Identification of Gemfibrozil Metabolites, Produced as Positional Isomers in Human Liver Microsomes, by On-line Analyses Using Liquid Chromatography/Mass Spectrometry and Liquid Chromatography/Nuclear Magnetic Resonance Spectroscopy

Kinetics of norethindrone in women; II. Single‐dose kinetics

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