Distribution Metabolism and Excretion

Argatroban distributes mainly in the extracellular fluid, with a steady state volume of distribution of 174 mL/kg (Swan and Hursting, 2000). It is 54% serum protein-bound (Tatsuno et al., 1986).

Unlike r-hirudin and bivalirudin, argatroban undergoes no significant renal clearance. The main route of metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver (Izawa et al., 1986). In vitro, the human liver microsomal cytochrome P450 3A4/5 (CYP3A4/5) catalyzes the formation of each of the four known metabolites. In plasma, unchanged argatroban is the major component, while the concentration of the primary metabolite (M1),

FIGURE 1 Chemical structure of argatroban. Its chemical name is 1-[5-[(ammoimino methyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]-pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate, and its molecular weight is 526.66.

FIGURE 2 (See color insert.) Model of the interaction between argatroban and thrombin.

which has three- to fivefold less activity than argatroban, is 0-20% of the parent drug (Ahsan et al., 1997). The other metabolites have not been detected in plasma or feces and are found only in very low quantities in urine. These data, together with the lack of effect of erythromycin, a potent CYP3A4/5 inhibitor, on argatroban pharmacokinetics (Tran et al., 1999) suggest that CYP3A4/5-mediated metabolism is not an important pathway in vivo.

Systemic clearance of argatroban is approximately 5.1 mL/min/kg for infusion doses up to 40 mg/kg/min in healthy volunteers (Swan et al., 2000). Its elimination half-life is 39-51 min (Swan and Hursting, 2000), with excretion primarily via the feces, presumably by biliary secretion.

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