Characterization of the urinary metabolites of dipetarudin

Dipetarudin is a hybrid thrombin inhibitor composed of the N-terminal structure of dipetalogastin II and the exosite 1 blocking segment of hirudin. Pharmacokinetic studies demonstrated that it distributes in extravascular and intravascular spaces and is exclusively eliminated by the kidneys. Two active metabolites of dipetarudin with molecular masses of 6142 and 5395 Da, respectively, were isolated from rat urine. Analysis of their N-terminal sequences and molecular masses demonstrated that dipetarudin is cleaved in a first step at the peptide bond Phe55Glu56 and then, at Gly3Asn4. Nonmetabolized dipetarudin was not found in rat urine. Proteases localized in the proximal tubulus cells of kidneys might be responsible for its degradation.