Received for publication August 29, 2005.
Revised November 9, 2005.
Accepted for publication November 10, 2005.

DEMONSTRATION OF DOCOSAHEXAENOIC ACID (DHA) AS A BIOAVAILABILITY ENHANCER FOR CYP3A SUBSTRATES: IN VITRO AND IN VIVO EVIDENCE USING CYCLOPORIN IN RATS

Abstract

In order to investigate pharmacokinetic interaction between cyclosporin A (CsA) and docosahexaenoic acid (DHA) in vivo, 5 mg/kg CsA was orally or intravenously co-administered with DHA (50-200 µg/kg) into rats. 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 co-administration of CsA with 100 and 200 µg/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 6-hydroxytestosterone from testosterone in rat liver microsomes was competitively inhibited by DHA. The K_m, V_max and K_i values were 25.5 µM, 2.45 nmol/min/mg-protein and 5.52 µM, respectively. Moreover, basal-to-apical transport of [³H]-CsA in the Caco-2 cell monolayer was not affected by DHA but was decreased by 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 which are extensively metabolized by CYP 3A in the gut.

Key words: CYP inhibition, CYP3A, drug absorption, drug clearance, drug interactions, first-pass metabolism, immunosuppression, oral absorption, pharmacokinetics