Effect of interferon α-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and N-acetyltransferase-2 activities in patients with chronic active hepatitis C

Background Interferon α (IFN-α) is thought to be responsible for cytochrome P450 (CYP)-dependent drug interactions mediated by a decrease in CYP activities. Objectives The objectives are to determine whether IFN-α and ribavirin can alter pretreatment CYP1A2, CYP2D6, CYP3A4 and N-acetyltransferase-2 activities after 1 month of treatment. Methods Enzymatic activities were determined among 14 patients with chronic active hepatitis C before IFN-α (3 · 106 U, 3 times a week) and ribavirin introduction and after 1 month of treatment. During both study periods, subjects received 80 mg dextromethorphan and 140 mg caffeine (1,3,7-trimethylxanthine [137X]). CYP3A4, CYP2D6, and NAT2 activities were assessed by use of urinary metabolic ratios of 3-methoxymorphinan/dextromethorphan, dextrorphan/dextromethorphan, and 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine(1X). The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity. Results CYP3A4 and CYP2D6 activities tended to increase after 1 month of antiviral therapy, but the change did not reach statistical significance. CYP1A2 and NAT2 activities were not significantly modified after 1 month of antiviral treatment. Pretreatment activities were significantly lower than those previously observed in healthy volunteers for CYP2D6 (mean ± SD, 148 ± 139 versus 759 ± 692; P = .0008) and CYP3A4 (0.18 ± 0.06 versus 0.52 ± 0.72; P = .0006). This difference was no longer statistically significant after 1 month of treatment, because CYP2D6 and CYP3A4 activities improved in 7 patients. Conclusion In patients with chronic hepatitis C, pretreatment CYP3A4 and CYP2D6 activities were significantly lower than those observed in healthy volunteers. These differences disappeared after 1 month of antiviral treatment because of the restoration of these CYP activities in about half of the patients. Clinical Pharmacology & Therapeutics (2002) 71, 488–495; doi: 10.1067/mcp.2002.124468