TISSUE DISTRIBUTION KINETICS OF A NEW NONSTEROIDAL 5A-REDUCTASE INHIBITOR, PHENYL)METHYLAMINO]BENZOYL]-1H-INDOL-1-YL]-BUTYRIC ACID, IN RATS

The disposition of a new nonsteroidal 5 alpha-reductase inhibitor, 4-[ 3-[3-[bis(4-isobutylphenyl)methylamino] benzoyl]-1H-indol-1-yl]-butyri c acid (FK143), was investigated in rats. After intravenous administra tion 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/k g. There were no essential differences between the two doses in any pa rameters. The serum protein binding in vitro was very high (>99%). The unidirectional uptake clearance (CL1) to 13 tissues was determined by integration plot until 10 min after intravenous administration of 1 m g/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, epididym is, seminal vesicle, and prostate were slower than from the blood, the efflux rate constant (k(2)) and rate constants at a binding compartme nt (k(3) and k(4)) were assumed in the pharmacokinetic model. A correl ation was found between the binding potential of binding compartment ( k(3)/k(4)) and V-max of steroid 5 alpha-reductase, the target enzyme, suggesting that the levels of 5 alpha-reductase activity or that of as sociated substances are a primary determinant of the specific binding of FK143 in these tissues.