METABOLISM IS AN IMPORTANT ROUTE OF PENTAMIDINE ELIMINATION IN THE RAT - DISPOSITION OF C-14 PENTAMIDINE AND IDENTIFICATION OF METABOLITES IN URINE USING LIQUID CHROMATOGRAPHY-TANDEM MASS-SPECTROMETRY

This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of C-14-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22+/-2% (mean+/-S.D.) and 25+/-4% being detected in urine and faeces, respectively The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21+/-5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76+/-15% (mean+/-S.D.) of the total excreted radioactivity on day 1 and 97+/-1% on day 6. HPLC - tandem mass spectrometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.