Preclinical and in vitro assessment of the potential of D0870, an antifungal agent, for producing clinical drug interactions.
1. D0870, an azole antifungal agent, produced dose-related increases in total cytochrome P450 and aldrin epoxidase when administered as 14 daily oral doses (0, 0.5, 2.5 and 12.5 mg/kg/day) to the male rat. Administered as single doses, D0870 increased pentobarbitone-sleeping time in a dose-related manner. 2. In human hepatic microsomal incubations, D0870 produced pronounced inhibition of CYP2C9 (tolbutamide hydroxylase) and, to a lesser degree, CYP3A4 (testosterone 6beta-hydroxylase), but had more limited effects on CYP1A2, 2C19 and 2D6 activity. In comparison with ketoconazole, itraconazole and fluconazole, D0870 was the most potent inhibitor of CYP2C9 activity. It is predicted that D0870 may inhibit the in vivo clearance of CYP2C9 substrates by approximately 58%, thereby increasing their steady-state concentrations by 2.4 times, which would be of clinical significance for some compounds. 3. During incubation of [14C]-D0870 with cultured human hepatocytes for up to 72 h, two discrete metabolites (A and B) were formed. Formation of metabolite A was abolished by both quinidine and ketoconazole and is probably CYP3A4-mediated, whereas generation of metabolite B did not appear to be dependent on cytochrome P450. 4. D0870 has potential to produce both induction and inhibition of cytochrome P450 enzymes in man.
McKillop
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Drug Kinetics Group, Safety of Medicines Department, Zeneca Pharmaceuticals, Macclesfield, UK.
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McCormick
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Evans
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D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D008956:Models, Chemical; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000935:Antifungal Agents; D006993:Hypnotics and Sedatives; D014230:Triazoles; C058219:ICI 195739; D003577:Cytochrome P-450 Enzyme System; D010424:Pentobarbital