RT Journal Article SR Electronic T1 Tissue Distribution Kinetics of a New Nonsteroidal 5α-Reductase Inhibitor, 4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol1-yl]-butyric Acid, in Rats JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1051 OP 1058 VO 25 IS 9 A1 Masataka Katashima A1 Koujirou Yamamoto A1 Kaori Haraguchi A1 Yoji Tokuma A1 Takehisa Hata A1 Yasufumi Sawada A1 Tatsuji Iga YR 1997 UL http://dmd.aspetjournals.org/content/25/9/1051.abstract AB The disposition of a new nonsteroidal 5α-reductase inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyric acid (FK143), was investigated in rats. After intravenous administration of FK143 at 1 and 5 mg/kg, total body clearance, elimination half-life, and volume of distribution at steady-state were, respectively, 6.96 and 8.76 ml/min/kg, 10.31 and 9.83 hr, and 4.11 and 3.33 liters/kg. There were no essential differences between the two doses in any parameters. The serum protein binding in vitrowas very high (>99%). The unidirectional uptake clearance (CL1) to 13 tissues was determined by integration plot until 10 min after intravenous administration of 1 mg/kg. CL1 values were much smaller than blood flow rate in all tissues, including the prostate, the target organ, indicating that FK143 was transported from blood to tissues by a membrane-limited process. Since the elimination rates of FK143 from the liver, kidney, lung, epididymis, seminal vesicle, and prostate were slower than from the blood, the efflux rate constant (k2) and rate constants at a binding compartment (k3 and k4) were assumed in the pharmacokinetic model. A correlation was found between the binding potential of binding compartment (k3/k4) andVmax of steroid 5α-reductase, the target enzyme, suggesting that the levels of 5α-reductase activity or that of associated substances are a primary determinant of the specific binding of FK143 in these tissues. The American Society for Pharmacology and Experimental Therapeutics