Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.

The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitroThe last several years has seen a dramatic increase in our understanding of drug metabolism and drug-drug interactions that are mediated through the inhibition or induction of cytochrome P-450 (CYP) enzymes. This is due in part to advances in techniques collectively called "reaction phenotyping," and includes the use of cDNAexpressed enzymes, and human liver microsomal preparations in combination with chemical inhibitors and antibodies directed against specific CYPs. One of the most frequently prescribed classes of medications is the antidepressants, many of which are either substrates of CYP2D6 or CYP3A3 ր 4, or are inhibitors of these two CYP systems. With the large amount of data being produced, clinicians have been looking for a way to generalize information regarding the capacity of antidepressants to inhibit various CYPs.At least seven other studies have examined the relative inhibitory potencies of the SSRIs and their metabolites in relation to 2D6 mediated reactions. These reactions include sparteine to 2-dehydrosparteine (Crewe et al. 1992), dextromethorphan to dextrorphan (Otton et al. 1993), desipramine to 2-hydroxydesipramine (von , imipramine to 2-hydroxyimipramine (Skjelbo and Brøsen 1992;Ball et al. 1997), clomipramine to 8-hydroxyclomipramine (Nielsen et al. 1996), desmethylclomipramine to 8-hydroxydesmethylclomipramine (Nielsen et al. 1996), and metoprolol to ␣ -hydroxymetoprolol and O-demethylmetoprolol (Belpaire et al. 1998).One of the newer antidepressants, venlafaxine (VF), is a structurally novel compound of the phenylethylamine class. VF inhibits the presynaptic reuptake of serotonin, norepinephrine, and to a lesser extent dopamine (Muth et al. 1986). It has little to no affinity for ␣ -1 adrenergic, muscarinic, or histaminergic receptors, and does not inhibit monoamine oxidase (Muth et al. 1986). VF is effective as an antidepressant (Schweizer et al. 1994;Cunningham et al. 1994), and may have utility in the treatment of panic disorder (Geracioti 1995), and attention-deficit disorder (Findling et al. 1996).VF is biotransformed in the liver to O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (N,O-DV) (Muth et al. 1991). ODV has a receptor affinity profile similar to its parent compound VF, while the latter two metabolites have little if any affinity for the above receptor sites (Muth et al. 1991). Previous studies have shown that the biotransformation of VF to ODV is mediated by CYP2D6, and NDV via CYP3A3 ր 4, and possibly a second enzyme (Otton et al. 1996).We used an in vitro model of human liver microsomal preparations and of microsomes containing individual human cytochromes expressed by cDNA-transfected human lymphoblastoid cells, to evaluate the biotransformation of VF to its principal metabolites ODV and NDV over a large range of substrate concentrations. We also assessed the inhibitory po...

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