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 Phe55-Glu56 and then, at Gly3-Asn4. Nonmetabolized dipetarudin was not found in rat urine. Proteases localized in the proximal tubulus cells of kidneys might be responsible for its degradation.
López
Mercedes
M
Instituto Venezolano de Investigaciones Científicas (IVIC), Lab. de Trombosis Experimental, Centro de Biofísica y Bioquímica, Apartado 21827, Caracas 1020A, Venezuela. mercedesllz@hotmail.com
Nowak
Goetz
G
D000595:Amino Acid Sequence; D000818:Animals; D000991:Antithrombins / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D010450:Endopeptidases / Q000737:chemistry; D008969:Molecular Sequence Data; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000652:urine*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000991:Antithrombins; D011993:Recombinant Fusion Proteins; C493509:dipetarudin; D010450:Endopeptidases; C020097:ecarin