Pharmacokinetics of Intravenous and Oral l,2-O-Isopropylidene-3-O-3′-(N′,N′-dimethylamino-n- propyl)-D-glucofuranose Hydrochloride in the Dog as a Function of Dose and Characterization of Metabolites

Abstract

□ The pharmacokinetics of l,2-O-isopropylidene-3-O-3'-(N′,N′-dimethylamino-n-propyl)-D-glucofuranose hydrochloride (I) was studied in dogs at intravenous and oral doses of 1-50mg/kg. There was no significant difference between the electrón-capture GLC of the hep- tafluorobutyric derivative of I and the radiochemical assay of chloroform extracts of plasma and urine for 1- to 20-mg/kg doses. Urinary amounts of I measured by GLC were 20% lower than radioassays of chloroform extracts at the 50-mg/kg dose. The pharmacokinetics of intravenous I was described by a two-compartment body model with sequential plasma half-lives of 7.5±0.7 and 136±6min. No apparent dose-dependent pharmacokinetics for I was observed on intravenous or oral administration. The apparent volume of distribution of the central compartment, 13.1±0.7 liters, is approximately the volume of the total body water in a 20-kg dog. The apparent overall volume of distribution of 40.0±1.5 liters exceeds the total body water, indicative of sequestration of I in tissues. Total and renal clearances were 205±5 and 155±5ml/min, respectively. The high renal clearance of I indicated an excess of tubular secretion. Renal clearance of I was not dependent on urine flow nor urine pH. Recovery of radioactivity in the feces after I was intravenously administered was <1%. Plasma protein binding of I was <5%, and the erythrocyte–plasma water partition coefficient was approximately unity. Compounds excreted in urine were separated into chloroform- extractable (pH12), ethyl acetate-extractable (pH2), and unextractable fractions which were further characterized by TLC. A multiple-extraction system was developed to estimate relative amounts and intrinsic partition coefficients of these extractable compounds from radioactivity counts of scraped plates and was applied to the assay of these compounds in the urine after intravenous administration of I. There was a readily chloro- form-extractable metabolite with an apparent partition coefficient of 3.3 and Rf 0.43 on TLC in the systems used. This apparent major metabolite could account for 8% of the administered radioactivity. Minor chloroform-extractable metabolites (0.8—3.3%) had lower apparent partition coefficients (0.26) but Rf values of 0.28 and 0.44. Ethyl acetate-extractable compounds (1.3—2.7%) had an apparent partition coefficient of 0.81 with Rf values of 0.52 and 0.68. Three unextractable compounds had Rf values of 0.20,0.50, and 0.62 and accounted for 0.16,2.8, and 0.9% of the administered radioactivity.