The influence of oral contraceptives on the metabolism of methaqualone in man.

Oram, Marcia; Wilson, Keith A.; Burnett, David

doi:10.1111/j.1365-2125.1982.tb01989.x

Cited by 15 publications

(7 citation statements)

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“…T h e serum clearance of methaqualone was greater and the halflife shorter on Day 15 compared to Day 1, while the metabolic data on control men was found to be similar to the female data measured on Day 1. An extension of this work showed that the increased metabolism shown on Day 15 was suppressed in females receiving oral contraceptives (52). T h e 24-h pattern of drug and metabolites in this study is shown in Fig.…”

Section: Body Rhythmssupporting

confidence: 56%

Factors Contributing to Variability in Drug Pharmacokinetics. Iii. Metabolism

Jack

2008

Journal of Clinical Pharmacy and Therapeutics

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Section: Body Rhythmssupporting

confidence: 56%

Factors Contributing to Variability in Drug Pharmacokinetics. Iii. Metabolism

Jack

2008

Journal of Clinical Pharmacy and Therapeutics

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“…Our more recent studies (Oram et al, 1982) have shown that the mid-cycle increase in the rate of methaqualone metabolism and clearance was abolished by oral contraceptive therapy and that the rate of metabolism of methaqualone in women receiving such therapy was similar to that on day 1 of a menstrual cycle in women not receiving oral contraceptives and to that in a control group of men. This provides strong circumstantial evidence for the view that the mechanism responsible for the mid-cycle increase in methaqualone metabolism involved the direct action of one or more hormones on hepatic enzymic activity.…”

Section: Studymentioning

confidence: 79%

The influence of the menstrual cycle on the metabolism and clearance of methaqualone.

Wilson¹,

Oram²,

Ce³

et al. 1982

Brit J Clinical Pharma

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1 The rate of methaqualone metabolism in women was shown to be significantly increased at the time of ovulation. 2 The apparent first order rate constants for the formation of five C-monohydroxy metabolites of methaqualone on day 15 of the menstrual cycle were approximately double that on day 1. 3 The N-oxidation of methaqualone showed considerable inter-individual variation in its sensitivity to the menstrual cycle, and in a group of ten women the difference in N-oxide excretion between days I and 15 was not statistically significant. 4 The serum clearance of methaqualone on day 15 was higher (mean value 94.6 ml min-' on day 1, 176.0 ml min-' on day 15), serum half-life shorter (mean ty,2 ( 16.3 h on day 1, 11.6 h on day 15) and the AUCGO smaller (mean value 44.0 ,ug ml-' h on day 1, 24.4 ,ug ml-' h on day 15) than on day 1. 5 The relative importance of the five hydroxy metabolites was unchanged during the menstrual cycle but the C/N oxidation ratio was greater on day 15 than on day 1. 6 The data for methaqualone metabolism in a control group of men was similar to that in women on day 1 of a menstrual cycle. ]IntroductionIn the rat, sex-related differences in the hepatic metabolism of drug and steroid hormones have been established (Skett & Gustafsson 1979;Mode et al., 1980;Mode et al., 1981 reported that the elimination half-life of chlordiazepoxide was longer and protein binding less in women than in men. Whereas the weight-normalised plasma clearance of total drug was the same in the two sexes, the clearance of unbound drug was significantly less in women than in men.Many of the human studies have been complicated by the fact that no attempt was made to control the time within a menstrual cycle when the female subjects were investigated. The cyclic variation in circulating hormone levels and the associated physiological changes that occur in premenopausal women may reasonably be expected to alter the distribution and metabolic clearance of drugs. The 0306-5251/82/090333-07 $01.00 literature evidence to support this expectation is conflicting. Thus a study by Wojcicki et al. (1979) using paracetamol identified a number of pharmacokinetic parameters that were significantly different during the follicular and luteal phases of a cycle and Kellermann et al. (1976) In our previous study of the inter-and intraindividual variation in the metabolism of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone) we concluded that its C-oxidation may be sensitive to cyclic variations in hormone levels (Wilson et al., 1978). The present study was carried out in order to investigate the effect of the menstrual cycle on the metabolism of methaqualone, the C-oxidation of which gives rise to the 2-, 2'-, 3'-, 4'-and 6-hydroxy

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“…However, a multiple regression analysis of their data led Mucklow et al (1980) to conclude that it was unlikely that environmental factors (cigarette smoking, alcohol, coffee, tea, diet) were the major determinants of interindividual variations in paracetamol conjugation. Oram et al (1982) have studied the effect of OCs, of the combined oestrogen-progestagen type, on the metabolic clearance of methaqualone. They found that the hormonal steroids abolished the midcycle increase in the rate of methaqualone metabolism previously observed in women not receiving OCs (Wilson et aI., 1982).…”

Section: Drug Kineticsmentioning

confidence: 99%

Sex-Related Differences in Drug Disposition in Man

Wilson¹

1984

Clinical Pharmacokinetics

154

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Sex-related differences in the disposition of some analgesics, anxiolytics and hypnotics have recently been reported. With certain benzodiazepines, sex has been shown to be a more important determinant of variability in drug disposition than age, while with other benzodiazepines an age-related decline in clearance was more pronounced in men than women. In young healthy adults these sex-related differences in drug disposition were related to the phase of the menstrual cycle, oral contraceptive steroid administration, and variations in plasma concentrations of albumin, alpha 1-acid glycoprotein, free fatty acids and sex hormones. While none of the sex-related differences so far reported necessitates the modification of a therapeutic dosage regimen, it is prudent that future protocols for pharmacokinetic studies should regard age, sex, the menstrual cycle and oral contraceptive steroids as potential sources of variability.

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The influence of oral contraceptives on the metabolism of methaqualone in man.

Cited by 15 publications

References 10 publications

Factors Contributing to Variability in Drug Pharmacokinetics. Iii. Metabolism

Factors Contributing to Variability in Drug Pharmacokinetics. Iii. Metabolism

The influence of the menstrual cycle on the metabolism and clearance of methaqualone.

Sex-Related Differences in Drug Disposition in Man

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