Disposition of (-)carbovir in the in situ perfused rat liver and intestinal vasculature preparations.
Carbovir (CBV), a carbocyclic nucleoside analog, is a potent and selective inhibitor of human immunodeficiency virus in human T-cells at noncytotoxic concentrations. Previous pharmacokinetic studies of (-)CBV in the rat showed nonlinearity in both the renal and nonrenal clearances and an oral bioavailability of 20%. This study was designed to evaluate the contribution of the rat liver and intestine to the first-pass effect of (-)CBV. The elimination of (-)CBV by the rat liver and intestine and the saturability of these processes were investigated with recirculating in situ perfused rat liver and intestinal vasculature preparations. Male Sprague-Dawley rats were used as liver (N = 11) or intestine (N = 3) donors. The recirculating perfusion studies were conducted with initial (-)CBV inflow concentrations ranging between 1.0-50 micrograms/ml for the liver perfusions and between 0.15-2.5 micrograms/ml for the intestinal perfusions. The hepatic elimination of (-)CBV was linear in the concentration range studied, with an instantaneous extraction ratio of 0.104 +/- 0.026 and an intrinsic clearance of 1.09 +/- 0.41 ml/min. The rat intestine did not extract (-)CBV. These studies indicate that the rat liver and intestine are not responsible for either the nonlinearity in nonrenal clearance or the low oral bioavailability observed in vivo.
Soria
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Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Zimmerman
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D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply; D008099:Liver / Q000378:metabolism*; D008297:Male; D009929:Organ Size; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir