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

1. Oxidative phosphorylation was studied in a cell-free preparation of Mycobacterium phlei and in rat-liver mitochondria. Phosphorylation was destroyed in both systems by long-wave ultraviolet radiation and restored by the addition of small amounts of [2-Me-(14)C,(3)H]phylloquinone. When the radioactive quinones were recovered from the phosphorylating system and chromatographed with carrier phylloquinone and menaquinone-4 in adsorption and partition systems, only the phylloquinone band was labelled, and its isotopic ratio was identical with that of the original [2-Me-(14)C,(3)H]phylloquinone. This result does not support the contention that the role of vitamin K in oxidative phosphorylation involves a cyclic mechanism with intermediate formation of a quinone methide. 2. When the [2-Me-(14)C,(3)H]phylloquinone was given intravenously to rats and radioactive phylloquinone isolated from their liver mitochondria and microsomes 20hr. later, its isotopic ratio was unchanged. There was thus no evidence for quinone methide formation in vivo. No measurable conversion of phylloquinone into menaquinone-4 was observed. 3. When [(14)C]menadione was given intraperitoneally to rats whose alimentary tract had been treated with neomycin, conversion into menaquinone-4 was found in the liver mitochondria and microsomes, but there was also some indication that there had been synthesis of phylloquinone.