PHARMACOKINETICS OF SM-10888 AND ITS METABOLITES DEPENDING ON THEIR PHYSICOCHEMICAL PROPERTIES

To investigate how the physicochemical properties and pharmacokinetics of SM-10888 are altered by metabolic reactions, physicochemical and p harmacokinetic parameters of its phase I and phase II metabolites were determined. The metabolic pathways of SM-10888 in rats include oxidat ion at the C-1 position (via the hydroxylated metabolite M(3) to the c yclic ketone M(4)) and glucuronidation of both SM-10888 and M(3) (SMG and M(3)G). Partition coefficients between n-octanol/pH 7.4 buffer (lo gP) were determined to be 2.23 for SM-10888, 1.59 for M(3), 2.66 for M(4), -1.37 for SMG, and -1.72 for M(3)G. The phase I metabolite M(3) showed lower lipophilicity and serum protein binding at pH 7.4, and la rger renal clearance (CL(r)) than SM-10888. In contrast, the further o xidized metabolite M(4) demonstrated higher lipophilicity and protein binding and lower CL, than SM-10888 and M(3). Among these nonconjugate d forms, only the pK(a) value of M(4) was found to be below 7.4 (6.2 f or M(4), 8.5 for SM-10888, and 8.0 for M(3)), indicating that Mg exist s in a more lipophilic nonionized form at the physiological pH, wherea s SM-10888 and M(3) are present as ionized forms. The significant shif t in pK(a) of M(4) 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 it s high lipophilicity and low CL(r). Glucuronidation significantly incr eased hydrophilicity with CL(r)'s in excess of the glomerular filtrati on rate, suggesting involvement of active transport.