Effect of fusidic acid on the hepatic cytochrome P450 enzyme system

Objective: To investigate the effects of fusidic acid therapy on the hepati c cytochrome P450 (CYP450) enzyme system. Methods: Thirty HIV-seropositive L-methadone-substituted i.v. drug abusers (stage CDC/WHO B2-3 with CD4(+)-c ounts ranging from 65 to 293/mu l) were randomized into 3 groups (A-C). Ten patients were treated with fusidic acid 500 mg/day over a period of 14 (gr oup A) or 28 days (group B), respectively. Patients in group C served as a control group and did not receive any medication apart from L-methadone. In order to investigate the hepatic monooxygenase system, pharmacokinetics we re determined in all patients before initiation and 14 and 28 days after st arting therapy with fusidic acid. The concentration of antipyrine and its 3 main metabolites (norantipyrine (NORA), 4-hydroxyantipyrine (OHA), 3 -hydr oxymethylantipyrine (HMA)) in plasma and urine were measured by high-perfor mance liquid chromatography (HPLC). Results: No effects on antipyrine pharm acokinetics and pharmacokinetics of antipyrine metabolites were found in gr oup A after 14 days of fusidic acid intake and in the control group without therapy. However, in contrast an activation of the CYP450 enzyme system wa s observed in group B after 28 days of fusidic acid therapy with an increas e of total antipyrine clearance (43.0 +/- 7.62 ml/min to 51.0 +/- 9.03 ml/m in) as well as clearances to all metabolites (NORA 7.11 +/- 1.75 to 8.60 +/ - 2.10 ml/min, OHA 11.5 +/- 2.89 to 14.0 +/- 3.97 ml/min, HMA 4.05 +/- 0.99 to 4.94 +/- 1.27 ml/min). Antipyrine half-life was significantly reduced ( 12.3 +/- 2.8 h to 9.4 +/- 2.2 h) and some patients developed clinical signs of L-methadone underdosage. Conclusions: Our results suggest that fusidic acid has a time-dependent activating effect on the CYP450 enzyme system. Es pecially in treatment of patients who are frequently under multidrug regime ns such as HIV-positive patients drug interactions should be taken into con sideration.