Two papers will come to be recognised as pivotal contributions to our understanding of the mechanism of ritonavir changes in drug disposition.

Paper 1 provides clear evidence (data in healthy volunteers) that the effect of ritonavir on methadone clearance results from increased renal clearance and induced hepatic metabolism. It is important to note that the induction of methadone metabolism occurred despite profound CYP inhibition in both intestine and liver (the expected effect). So these data clearly suggest that there is no role for CYP3A4 in methadone metabolism.

Paper 2 describes short term (2 day) and steady-state (2 week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with iv and oral alfentanyl) and P-gp (probed with fexofenadine), and on methadone pharmacokinetics in healthy volunteers. The authors conclude that acute ritonavir inhibits hepatic CYP3A (>70%) and first pass CYP3A (>90%). The fexofenadine data suggested P-gp inhibition. While mild induction of P-gp and hepatic CYP3A by steady state ritonavir was apparent, the overall net effect was still marked inhibition.

References

1. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. _Kharasch E, Bedynek P, Park S, et al. _Clin Pharmacol Ther, 2008, 84(4): 497-505.
http://www.ncbi.nlm.nih.gov/pubmed/18615008
2. Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities._Kharasch E, Bedynek P, Walker A, et al. Clin Pharmacol Ther, 2008, 84(4): 506-512.
http://www.ncbi.nlm.nih.gov/pubmed/18615009
Source: www.hiv-druginteractions.org (3 October 2008).
http://www.hiv-druginteractions.org/frames.asp?new/Content.asp?ID=398