INHIBITION OF DESIPRAMINE HYDROXYLATION (CYTOCHROME P450-2D6) IN-VITRO BY QUINIDINE AND BY VIRAL PROTEASE INHIBITORS - RELATION TO DRUG-INTERACTIONS IN-VIVO

Pharmacokinetic drug interactions with viral protease inhibitors are o f potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhib itors with substrates of cytochrome P450-2D6. Biotransformation of des ipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhib itors currently used to treat human immunodeficiency virus infection w ere tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean K-m value of 11.7 mu M (range: 9.9-15.3 mu M). Quinidine, a highly pot ent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mea n inhibition constant of 0.16 mu M (range: 0.13-0.18 mu M). All four p rotease inhibitors impaired OH-DMI formation; the pattern was consiste nt with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were a s follows: ritonavir, 4.8 mu M; indinavir, 15.6 mu M; saquinavir, 24.0 mu M; nelfinavir, 51.9 mu M. In a clinical pharmacokinetic study, coa dministration of ritonavir with DMI inhibited DMI clearance by an aver age of 59%. The in vitro findings, together with observed plasma riton avir concentrations, provided a reasonable quantitative forecast of th is interaction, whereas estimated unbound plasma or intrahepatic riton avir concentrations yielded poor quantitative forecasts, Thus the in v itro model correctly identifies ritonavir as a potent and clinically i mportant inhibitor of human P450-2D6. Other protease inhibitors may al so inhibit 2D6 activity in humans, but with lower potency than ritonav ir.