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

Abstract

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

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

“…The results of our study indicate that oral contraceptives of the combined oestrogen-progestogen type abolish the mid-menstrual cycle increase in the rate of methaqualone metabolism (Figure 1, Table 2) previously observed in healthy women (Wilson et al, 1982). This effect of the combined oral contraceptives was obtained after as little as one months' therapy (Table 3) so that the long-term consequences of oral contraceptive therapy on liver size (Homeida et al, 1978) are not essential for this effect.…”

“…Our data with methaqualone can be used to support the indirect mechanism hypothesis of O' Malley et al (1972). The fact that combined oral contraceptive therapy eliminated the increased rate of metabolic clearance of methaqualone observed at the time of ovulation in women not receiving the steroids and resulted in a metabolic rate and pattern similar to that seen in women on days 1, 8 and 22 of a cycle and in a control group of men (Wilson et al, 1982) would be rather fortuitous if it involved a purely competitive mechanism, especially as a comparatively large dose (250 mg) of drug was involved. The concept that the steroid contraceptives inhibited a hormonal control of hepatic metabolism is a more attractive mechanism which is more consistent with the contraceptive action of the steroids.…”

“…In view of our recent observation that the rate of methaqualone metabolism in healthy women is significantly increased at the time of ovulation (Wilson et al, 1982), we have investigated the effect of oral contraceptive therapy on methaqualone metabolism. 0306-5251/82/090341-05 $01.00 Methaqualone is cleared solely by metabolism to five C-monohydroXy metabolites and an N-oxide .…”

Sex-Related Differences in Drug Disposition in Man

“…apparently without a concomitant change in apparent volume of distribution, indicated a change in hepatic clearance as a consequence of a change in intrinsic clearance, hepatic blood flow or protein binding. Methaqualone in normal subjects is highly protein bound (Smart and Brown, 1970), and Backstrom and Jorpes (1979) have shown that no variation occurs in albumin concentration during a menstrual cycle, but variations in lipoproteins and ai-acid glycoprotein during a cycle have not been investigated, and Wilson et al (1982) did not study the effect of the menstrual cycle on the binding characteristics of methaqualone.…”

Salivary paracetamol elimination kinetics during the menstrual cycle.

“…The disposition of antipyrine has been reported to be differentially altered on specific days of the menstrual cycle (Riester et al, 1980;Kellermann et al, 1976). The most positive evidence for the influence of menstrual cycle on drug kinetics has come from the studies with methaqualone Wilson et al, 1982). We have investigated paracetamol elimination kinetics on different days of the menstrual cycle.…”