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First published on May 12, 2006; DOI: 10.1124/dmd.106.009258

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Received for publication January 11, 2006.
Revised May 3, 2006.
Accepted for publication May 5, 2006.

IN VITRO AND IN VIVO CORRELATION OF HEPATIC TRANSPORTER EFFECTS ON ERYTHROMYCIN METABOLISM: CHARACTERIZING THE IMPORTANCE OF TRANSPORTER-ENZYME INTERPLAY

Justine Lam 1, Hideaki Okochi 1, Yong Huang 1, Leslie Z Benet 1*

1 UCSF

* Address correspondence to: E-mail: benet{at}itsa.ucsf.edu

Abstract

The effects of hepatic uptake and efflux transporters on ERY disposition and metabolism were examined by comparing results from rat hepatic microsomes, freshly isolated hepatocytes and in vivo studies. Uptake studies carried out in freshly isolated rat hepatocytes showed that ERY and its metabolite (N- demethyl-ERY) are substrates of Oatp1a4 and Oatp1b2. While rifampin and GG918 exerted minimal effects on metabolism in microsomes, rifampin (2.5µM) and GG918 (0.5µM) significantly decreased and increased ERY metabolism in hepatocytes, respectively. Concentrationtime course studies further demonstrated that compared to the intracellular N-demethyl- ERY control AUC (0.795 ± 0.057 µM·min), a decreased AUC (0.513 ± 0.028 µM·min, p<0.005) was observed when ERY was co-incubated with rifampin, and an increased AUC (2.14 ± 0.21 µM·min, p<0.05) was found when GG918 was present. The results of the i.v. bolus studies showed that compared to the ERY clearance of the controls (47.2 ± 12.5 ml/min/kg for rifampin group and 42.1 ± 5.7 for GG918 group), a decreased CLblood, 29.8 ± 6.1 ml/min/kg (p<0.05) and 21.7 ± 9.0 ml/min/kg (p<0.01), were observed when rifampin or GG918 was co-administered, respectively. When either inhibitor was codosed with ERY, Vss was unchanged but T1/2 and MRT significantly increased compared to the controls. Hepatic uptake and efflux transporters modulate intracellular concentrations of ERY, thereby affecting metabolism. The interplay of transporters and enzymes must be considered in evaluating potential drug- drug interactions.


Key words: cytochrome P450, drug transport, drug-drug interactions, first-pass metabolism, membrane transport, organic anion transport, p-glycoprotein, pharmacokinetics


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