Rx focus Drug Get to Know an : Interactions CYP2C8 John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD

n previous issues of Pharmacy Times, in about 20% of whites, but is rare in Importance of Drug we discussed other members of the blacks. Patients who are homozygous Interactions Involving CYP2C8 Icytochrome P450 (CYP) 2C family, (CYP2C8*2/*2 or CYP2C8*3/*3) have Perhaps the most important drug inter- CYP2C9 and CYP2C19. In this issue, we lower intrinsic clearance of CYP2C8 sub- action involving CYP2C8 was the inter- will discuss CYP2C8—an enzyme whose strates than those who are heterozygous action between cerivastatin and gemfi- importance in the metabolism of reti- (CYP2C8*1/*2 or CYP2C8*1/*3). brozil. Cerivastatin was the only noic acid and has been primarily metabolized by CYP2C8. recognized for many years, but which CYP2C8 Substrates When (an inhibitor of both has only recently been associated with Some of the drugs identified as substrates CYP2C8 and organic anion-transporting the metabolism of a number of common for CYP2C8 are listed in Table 1. Many polypeptide─mediated elimination of therapeutic agents. drugs are metabolized by more than 1 cerivastatin) was administered in combi- The enzyme CYP2C8 constitutes about CYP enzyme, and this is especially true nation with cerivastatin, the risk of devel- 7% of the cytochrome content in the liver.1 for CYP2C8, where it is often a second- oping rhabdomyolysis increased greatly. Additionally, CYP2C8 protein has been ary pathway. Nonetheless, there are some As a result, cerivastatin was removed from detected in the intestine, kidneys, and drugs for which CYP2C8 is known to be the market. brain. CYP2C8 is known to convert arachi- an important pathway, and these are listed Because drugs metabolized by donic acid in the kidneys to active metabo- with an asterisk (*) in Table 1. CYP2C8 often have other pathways, lites that influence sodium transport, water if the patient is genetically deficient in reabsorption, and vascular tone. Table 2 one of the other pathways or is admin- istered an inhibitor of an alternative CYP2C8 Inhibitors Genetic Influences pathway, inhibition of CYP2C8 may Racial background is an important fac- Deferasirox (Exjade) become more important. tor in the likelihood of being deficient Gemfibrozil (Lopid) is metabolized by both CYP2C8 and in CYP2C8. The common variants are CYP3A4. When subjects receiving repa- (Tykerb) CYP2C8*2 and CYP2C8*3, both having glinide were concurrently administered reduced activity compared with the nor- Trimethoprim (Septra, Trimpex) itraconazole (inhibition of CYP3A4) or mal form. About 15% of black patients CYP = . gemfibrozil, the area under the concen- have the CYP2C8*2 variant; however, tration time curve (AUC) of repaglinide this variant is very rare (<1%) in white increased by 40% and 8-fold, respec- patients. The CYP2C8*3 variant is found CYP2C8 Inhibitors tively, compared with repaglinide alone. Drugs that inhibit CYP2C8 activity (Table When itraconazole and gemfibrozil were Table 1 2) are likely to increase the plasma con- coadministered, the AUC of repaglinide CYP2C8 Substrates centrations of the medications listed with increased about 20-fold.3 an asterisk in Table 1, and in some cases Amiodarone (Cordarone) adverse outcomes may occur. For the Summary Cabazitaxel (Jevtana) other drugs in Table 1, for which other The cytochrome P450 enzyme CYP2C8 is Carbamazepine (Tegretol) may be more important, the out- at least partly involved in the metabolism come of the interaction is more difficult of a number of drugs, but inhibitors of Chloroquine* (Aralen) to predict. CYP2C8 will tend to have the greatest (Voltaren) effect on drugs for which CYP2C8 is the Ibuprofen (Advil) CYP2C8 Inducers primary pathway. But CYP2C8 inhibition The only drug that has been shown to by itself may not cause toxicity because * (Taxol) induce (stimulate) CYP2C8 in vivo is for many of the drugs that are substrates * (Avandia) rifampin. Rifampin is known to induce of CYP2C8, the alternative pathways Repaglinide* (Prandin) several drug metabolism pathways, so it is often take over. Nonetheless, inhibition or likely to reduce the plasma concentration induction of CYP2C8 sometimes results in Treprostinil (Tyvaso) of CYP2C8 substrates even if they have adverse drug interactions, so it should not CYP = cytochrome P450. multiple pathways of elimination. Enzyme be ignored. PT *Drugs for which CYP2C8 is a primary pathway. inducers tend to be “broad spectrum,” in that they often induce several CYP iso- Drs. Horn and Hansten are both professors of pharmacy zymes, so it is possible that other inducers › Web .com at the University of Washington School of Pharmacy. For (eg, phenobarbital, St. John’s wort) may an electronic version of this article, including references For a list of references, go to www.PharmacyTimes.com/ if any, visit www.hanstenandhorn.com. also induce CYP2C8. publications/issue/2011/December2011.

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