Influence of Renal and Hepatic Failure on the Pharmacokinetics of Argatroban: An Experimental Study in Rats

ABSTRACT

A model of functional nephrectomy and hepatectomy in rats was used to compare the pharmacokinetic profile of the direct competitive thrombin inhibitor argatroban in rats with renal, hepatic, or hepatorenal failure and rats with normal hepatic and renal function. The pharmacokinetics of argatroban in rats after an intravenous bolus was described by an open two-compartment model with first-order elimination. This profile was not affected in nephrectomized rats, but hepatectomized rats showed a markedly increase in area under the curve values, distribution, and elimination half-life in comparison with untreated rats as expected for a drug eliminated primarily by the liver. Unexpectedly, blood levels of argatroban were lower in rats with hepatorenal failure than in rats with only hepatic failure. Similar results were observed after subcutaneous administration of argatroban. We propose that argatroban might be converted from 21–(R) to 21-(S) diastereoisomer in the kidneys. The 21-(S) diastereoisomer has a higher antithrombotic activity than the R isoform and this 21-(S) isomer might be preferentially hepatically eliminated. This could explain the higher anticoagulant activity in blood of hepatectomized rats with normal renal function in comparison with rats with hepatorenal failure.

KEYWORDS

Argatroban - pharmacokinetics - renal failure - hepatic failure - hepatorenal failure

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