Ritonavir's role in reducing fentanyl clearance and prolonging its half-life

Background The human immunodeficiency virus protease inhibitor ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme, and ritonavir's conc omitant administration with the substrates of this enzyme may lead to dange rous drug interactions. Methods: The authors investigated possible interactions between ritonavir a nd intravenously administered fentanyl in a double-blind, placebo-controlle d, cross-over study in two phases. Twelve healthy volunteers received orall y ritonavir or placebo for 3 days; the dose of ritonavir was 200 mg three t imes on the first day and 300 mg three times on the second. The last dose o f ritonavir 300 mg or placebo was given on the morning of the third day. On the second day, 2 h after the afternoon pretreatment dose, fentanyl 5 mu g /kg was injected intravenously in 2 min with naloxone to moderate its effec ts, and 15 timed venous blood samples were collected for 18 h. Results: Ritonavir reduced the clearance of fentanyl by 67% from 15.6 +/- 8 .2 to 5.2 +/- 2.0 ml.min(-1).kg(-1) (P < 0.01). The area under the fentanyl plasma concentration-time curve from 0 to 18 h was increased from 4.8 +/- 2.7 to 8.8 +/- 2.3 ng.ml(-1).h(-1) by ritonavir (P < 0.01). Ritonavir did n ot affect the initial concentrations and the steady-state volume of distrib ution of fentanyl. One subject discontinued participation before fentanyl a dministration because of severe side effects, and during the study 8 of the remaining 11 subjects reported nausea. Conclusions: Ritonavir can inhibit the metabolism of fentanyl significantly , so caution should be exercised if fentanyl is given to patients receiving ritonavir medication.