Abstract

To investigate how the physicochemical properties and pharmacokinetics of SM-10888 are altered by metabolic reactions, physicochemical and pharmacokinetic parameters of its phase I and phase II metabolites were determined. The metabolic pathways of SM-10888 in rats include oxidation at the C1 position (via the hydroxylated metabolite M3 to the cyclic ketone M4) and glucuronidation of both SM-10888 and M3 (SMG and M3G). Partition coefficients between n-octanol/pH 7.4 buffer (logP*) were determined to be 2.23 for SM-10888, 1.59 for M3, 2.66 for M4, -1.37 for SMG, and -1.72 for M3G. The phase I metabolite M3 showed lower lipophilicity and serum protein binding at pH 7.4, and larger renal clearance (CLr) than SM-10888. In contrast, the further oxidized metabolite M4 demonstrated higher lipophilicity and protein binding and lower CLr than SM-10888 and M3. Among these nonconjugated forms, only the pKa value of M4 was found to be below 7.4 (6.2 for M4, 8.5 for SM-10888, and 8.0 for M3), indicating that M4 exists in a more lipophilic nonionized form at the physiological pH, whereas SM-10888 and M3 are present as ionized forms. The significant shift in pKa of M4 could be the result of a cooperative effect of the electron withdrawing carbonyl group and resonating structure allowing hydrogen bond formation between CO and NH2 group, and might explain its high lipophilicity and low CLr. Glucuronidation significantly increased hydrophilicity with CLr's in excess of the glomerular filtration rate, suggesting involvement of active transport.