Demonstration of docosahexaenoic acid as a bioavailability enhancer for CYP3A substrates: in vitro and in vivo evidence using cyclosporin in rats.

To investigate the pharmacokinetic interaction between cyclosporin A (CsA) and docosahexaenoic acid (DHA) in vivo, 5 mg/kg CsA was orally or intravenously coadministered with DHA (50-200 microg/kg) to rats. The effect of DHA on CYP3A activity was determined using rat liver microsomes in vitro. Moreover, the effect of DHA on P-glycoprotein (P-gp) function was examined using cultured Caco-2 cells in vitro. After oral coadministration of CsA with 100 microg/kg and 200 microg/kg DHA, bioavailability (BA) was significantly increased, compared with control rats. In contrast, no pharmacokinetic interaction was observed when CsA was intravenously administered in rats dosed orally with DHA, suggesting that DHA did not affect hepatic metabolism. The formation of 6beta-hydroxytestosterone from testosterone in rat liver microsomes was competitively inhibited by DHA. The Km, Vmax, and Ki values were 25.5 microM, 2.45 nmol/min/mg protein, and 5.52 microM, respectively. Moreover, basal-to-apical transport of [3H]CsA in the Caco-2 cell monolayer was not affected by DHA but was decreased by valspodar (PSC 833), a P-gp inhibitor. Our finding is the first to indicate that DHA inhibits intestinal CYP3A both in vitro and in vivo, but not P-gp. It was thus demonstrated that DHA could be used as a BA enhancer for the drugs that are extensively metabolized by CYP3A in the gut.