1 The metabolism of 17ot-ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2 2-Hydroxyethinyloestradiol (2-OHEE2) was either the sole or principal metabolite. Small amounts of 6-hydroxyethinyloestradiol and 16-hydroxyethinyloestradiol were produced by some of the livers.3 EE2 (10 /M) underwent substantial (5-20% of incubated drug), though highly variable, NADPH-dependent metabolism to material irreversibly bound to microsomal protein. 4 2-OHEE2 appeared to be the pro-reactive metabolite.5 The maximum EE2 2-hydroxylase activity was 0.67 nmol min-1 mg-' microsomal protein, with a Km value of 8.6 FLM. 6 Oestradiol, which is mainly hydroxylated to 2-hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. 7 Progesterone, which undergoes 2-hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. 8 Primaquine was the most potent non-steroidal inhibitor but was non-competitive. Other non-steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2-hydroxylation. 9 The results of this study suggest that EE2 2-hydroxylation is metabolised by a form(s) of cytochrome P-450 which has affinity for endogenous steroids.

1 Five patients have been studied to determine the contribution of the gut wall to the pre‐systemic metabolism of ethinyloestradiol. All patients had a catheter inserted into their hepatic portal vein as part of their surgical management. 2 After an oral dose of 50 micrograms (65 microCi) ethinyloestradiol, blood samples were taken from the hepatic portal vein and from a peripheral vein at intervals for 1 h. 3 In each patient the concentration of conjugated ethinyloestradiol in the portal vein was considerably higher than in the peripheral vein. 4 Although a number of assumptions have been made, calculations showed that the gut wall appeared to be twice as effective as the liver in conjugating ethinyloestradiol on the first pass. 5 In two patients there was no evidence of major uptake or metabolism of ethinyloestradiol in the lung.

1 The effects of two antimalarial drugs, chloroquine and primaquine on antipyrine kinetics and metabolism have been studied in volunteers. 2 Chloroquine (250 mg) given 2 h before antipyrine (600 mg orally) had no effect on salivary kinetics of antipyrine or on the urinary recovery of metabolites. Primaquine (45 mg) given 2 h before antipyrine (300 mg orally), increased antipyrine half-life (calculated from 0-24 h) from 12.7 + 3.2 (mean + s.d.) to 25.3 + 3.9hand decreased clearance from3.01 + 0.67 to 1.32 + 0.321 h-. There was no change in the apparent volume of distribution. Antipyrine half life changed with time in the presence of primaquine and when calculated between 24 and 48 h had returned to control. 3 After primaquine, the metabolic clearance (calculated from 0-24 h) of antipyrine to its three main metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine was significantly reduced. There was no selective effect on a particular metabolic pathway.4 There was no change in 6,8-hydroxycortisol excretion (expressed as a ratio of total 17-hydroxycorticosteroids) in the period 0-48 h following primaquine administration. 5 The inhibition of hepatic metabolism by primaquine but not the structurally related chloroquine may be an example of a structure activity phenomenon and could be of clinical significance.

No abstract

Eight samples of human liver have been characterised for microsomal protein content, cytochrome P450 content, tolbutamide 4-hydroxylase and ethinyloestradiol 2-hydroxylase activities. Cytochrome P-450 content correlated significantly with ethinyloestradiol 2-hydroxylase activity but not with tolbutamide 4-hydroxylase activity. There was no significant correlation between ethinyloestradiol 2-hydroxylase and tolbutamide 4-hydroxylase activities. The maximum tolbutamide 4-hydroxylase activity was 0.45 nmol min-' mg-1 microsomal protein, with a Km value of 74 FLM. A number of compounds were tested for their ability to inhibit tolbutamide metabolism. All the compounds showing inhibition were either non-competitive or mixed non-competitive inhibitors of tolbutamide 4-hydroxylation. These studies suggest that tolbutamide is metabolised by an isozyme of cytochrome P-450 which appears to be distinct from those isozymes metabolising many other drugs.