title: Tissue distribution kinetics of a new nonsteroidal 5 alpha-reductase [correction of 5 A-reductase] inhibitor, 4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-YL ]-butyric acid, in rats.
abstract: The disposition of a new nonsteroidal 5alpha-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 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 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) and V(max) of steroid 5alpha-reductase, the target enzyme, suggesting that the levels of 5alpha-reductase activity or that of associated substances are a primary determinant of the specific binding of FK143 in these tissues.
authors.affiliation: Pharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Katashima
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Haraguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Tokuma
authors.forename: T
authors.initials: T
authors.lastname: Hata
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Iga
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005753:Gastric Mucosa / Q000378:metabolism; D006207:Half-Life; D007211:Indoles / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D010654:Phenylbutyrates / Q000493:pharmacokinetics*; D011467:Prostate / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C093354:4-(3-(3-(bis(4-isobutylphenyl)methylamino)benzoyl)-1H-indol-1-yl)butyric acid; D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D010654:Phenylbutyrates