CYP-mediated drug interactions

Wahlstrom, J. L., Rock, D. A., Slatter, J. G., and Wienkers, L. C. (2006). Advances in predicting CYP-mediated drug interactions in the drug discovery setting. Expert Opin. Drug Discov. 1 677-691. 

Over the past decade there has been a substantial improvement in the ability to predict metabolism-based in vivo drug interactions from kinetic data obtained in vitro. This advance has been most evident for interactions that occur at the level of cytochrome P450 (CYP)-catalyzed oxidation and reflects the availability of human tissue samples, cDNA-expressed CYPs, and well-defined substrates and inhibitors of individual enzymes. The most common paradigm in the prediction of in vivo drug interactions has been first to determine the enzyme selectivity of a suspected inhibitor and subsequently to estimate the constant that quantifies the potency of reversible inhibition in vitro. This approach has been successful in identifying clinically important potent competitive inhibitors, such as quinidine, fluoxetine, and itraconazole. However, there is a continuing concern that a number of well-established and clinically important CYP-mediated drug interactions are not predictable from the classical approach that assumes reversible mechanisms of inhibition are ubiquitous. 

Lin JH. CYP induction-mediated drug interactions In vitro assessment and clinical implications. Pharm Res 2006 23 1089-1116. 

Rifampin Hepatic abnormalities monitor LFTs Reddish-orange discoloration of secretions (e.g., urine, sweat, tears) Potent inducer of CYP-mediated metabolism evaluate for drug-drug interactions... 

Drug interactions mediated by CYP enzymes in the bowel wall, liver, or transporters in the bowel wall... 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Members of this class of antidepressants are likely to be involved in pharmacodynamic and CYP-mediated pharmacokinetic drug-drug interactions. The latter are of concern because of the narrow therapeutic index of TCAs. 

In comparison with TCAs, SSRIs cause fewer pharmacodynamic drug-drug interactions but some (i.e., fluvoxamine, fluoxetine, paroxetine) cause more CYP enzyme mediated pharmacokinetic drug-drug interactions. Unlike TCAs, SSRIs do not potentiate alcohol and perhaps even slightly antagonize its acute CNS effects. Nevertheless, there are some important adverse interactions. 

Although venlafaxine can have more interactions than SSRIs pharmacodynamically, it is comparable with citalopram and sertraline in terms of not causing CYP enzyme mediated pharmacokinetic drug-drug interactions (Table 7-29). Thus, these three antidepressants have a distinct advantage over drugs such as fluoxetine, particularly in patients who are likely to be on other medications in aaaition to their antidepressant. 

Figure 2 Influence of fm (fraction metabolized by inhibited P450) on drug-drug interactions. The control represents a model drug for which cytochrome P450 (dark bar) is responsible for 20% of the clearance, with the remaining 80% being non-P450 mediated (white bar). CYP inhibited and CYP induced illustrate the effect on total clearance of a fivefold reduction or increase in the P450 activity, respectively.

As mentioned earlier, the underlying mechanisms for many of the transporter-mediated interactions are not fully understood and remain elusive at the present time. With the limited knowledge on the molecular mechanisms of transporter-mediated interaction and the fact that many inhibitors and inducers can simultaneously affect both drug transporters and CYP enzymes, it is difficult to quantitatively differentiate transporter-mediated interactions from CYP-mediated interactions. From the literature, it becomes clear that evidence of transporter-mediated dmg interactions, with few exceptions, is often indirectly derived from in vitro transport studies with cellular culture models and heterologous expression systems. 

As the examples cited above indicate, many clinical chug interactions have been considered to be mediated by inhibition or induction of transporters based only on circumstantial evidence. Because of the lack of potent and specific inhibitors for each transporter, it is difficult to accurately assess the relative contributions CYP enzymes and transporters in drug absorption and excretion. The mechanisms become even more complex when multiple CYP enzymes and drug transporters are involved in the processes of drug absorption and excretion. Therefore, care should be taken when exploring the underlying mechanism of drug interactions. 

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