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- Title
Effects of cytochrome P450 inducers on 17α-ethinyloestradiol (EE[sub 2]) conjugation by primary human hepatocytes.
- Authors
Li; Hartman; Lu; Collins; Strong
- Abstract
Aims Our objective was to elucidate further the underlying mechanism responsible for therapeutic failures observed with concomitant administration of the oral contraceptive 17α-ethinyloestradiol (EE[sub 2] ) and rifampicin. Methods We investigated both oxidative and direct conjugative [[sup 3]H]-EE[sub 2] metabolism by human liver S9 fraction and the effect of known enzyme-inducing drugs using a human hepatocyte induction model in vitro. Results Cofactor dependent [[sup 3]H]-EE[sub 2] metabolism by human liver S9 fraction produced 2-hydroxy-[[sup 3]H]-EE[sub 2], 2-methoxy-[[sup 3]H]-EE[sub 2], and direct [[sup 3]H]-EE[sub 2 ]sulphate and glucuronide conjugates. Only two detectable metabolites of [[sup 3]H]-EE[sub 2] were produced by the S9 fraction in the presence of all cofactors: [[sup 3]H]-EE[sub 2]–3-sulphate (75.7±7.6% s.d.) and 2-methoxy-[sup 3]H-EE[sub 2] (2.6%±0.5% s.d.). Human hepatocytes extensively metabolized [[sup 3]H]-EE[sub 2] to its glucuronide and sulphate conjugates. Small amounts of a 2-methoxy-[[sup 3]H]-EE[sub 2] 3-conjugate, ≤10%, was observed but no. 2-hydroxy-[[sup 3]H]-EE[sub 2] was detected. An unexpected finding in our study was increased [[sup 3]H]-EE[sub 2]–3-sulphate production (1.5–3.3 fold, n=3 donor livers) by hepatocytes pretreated with rifampicin compared to control hepatocytes. No statistically significant increase in [[sup 3]H]-EE[sub 2]–3-sulphation was observed in hepatocytes pretreated with 3-methylcholanthrene, phenobarbitone, dexamethasone, or omeprazole over nontreated hepatocytes. To our knowledge, this is the first observation of sulphotransferase induction by rifampicin in human hepatocytes in vitro resulting in increased [[sup 3]H]-EE[sub 2] sulphation. Conclusions Our data indicate that the major EE[sub 2] metabolic products formed by human hepatocytes in vitro are direct EE[sub 2] conjugates with EE[sub 2] oxidation representing minor pathways. Further studie...
- Subjects
SOUTH Carolina; HILTON Head (S.C.); UNITED States; ORAL contraceptives; RIFAMPIN
- Publication
British Journal of Clinical Pharmacology, 1999, Vol 48, Issue 5
- ISSN
0306-5251
- Publication type
Article