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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.

2,4',5-Trichlorobiphenyl (TriCB), 2,3',4',5-tetrachlorobiphenyl (TetraCB), 2,2',4',5,5'-pentachlorobiphenyl (PentaCB), and 2,2',3',4',5,5'-hexachlorobiphenyl (HexaCB) were studied with regard to the fecal excretion and tissue distribution of their metabolites after intraperitoneal injection to rats. Major fecal metabolites were 3- and 4-hydroxy and 3- and 4-methylthio derivatives, the substitution ratios depending largely on the degree of chlorination. As the degree of chlorination increased, hydroxy products were more efficiently excreted, whereas the formation of methylthio metabolites greatly decreased. As a result, the excretion ratios of methylthio and hydroxy products varied with 2.8 for TriCB, 1.3 for TetraCB, 0.04 for PentaCB, and 0.02 for HexaCB. The 3-/4-hydroxy substitution ratios were 0.6 for TriCB, 1.4 for TetraCB, 21 for PentaCB, and 35 for HexaCB, whereas the 3-/4-methythio substitution ratios were 1.2 for TriCB, 0.8 for TetraCB, 0.18 for PentaCB, and 0.12 for HexaCB. The formation rate of 3- and 4-methylthio metabolites from each congener was correlated to the accumulation and distribution of 3- and 4-methylsulfonyl derivatives in tissues. The tissue/blood concentration ratios of methylsulfonyl metabolites showed that the 3-methylsulfonyl derivatives from higher chlorinated biphenyls had a relatively high affinity for liver and adipose tissue, whereas the 4-methylsulfonyl derivatives were selectively retained in the lung in all cases.

It is known that catalepsy serves as an experimental animal model of parkinsonism. In this study, the relationship between in vivo dopamine D1 and D2 receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs that bind to D1 and D2 receptors nonselectively. 3H-SCH23390 and 3H-raclopride were used for the labeling of D1 and D2 receptors, respectively. The ternary complex model consisting of agonist or antagonist, receptor, and transducer was developed, and the dynamic parameters were determined. After coadministration of SCH23390 and nemonapride, catalepsy was stronger than sum of the values predicted by single administration of each drug, and it was intensified synergistically. This finding suggested the existence of interaction between D1 and D2 receptors, and the necessity for constructing the model including this interaction. To examine the validity of this model, catalepsy and in vivo dopamine receptor occupancy were measured after administration of drugs that induce or have a possibility to induce parkinsonism (haloperidol, flunarizine, manidipine, oxatomide, hydroxyzine, meclizine, and homochlorcycilzine). All of the tested drugs blocked both dopamine D1 and D2 receptors. Intensity of catalepsy was predicted with this dynamic model and was compared with the observed values. In contrast with haloperidol, flunarizine, manidipine, and oxatomide (which induced catalepsy), hydroxyzine, meclizine, and homochlorcyclizine failed to induce catalepsy. Intensities of catalepsy predicted with this dynamic model considering the interaction between D1 and D2 receptors overestimated the observed values, suggesting that these drugs have catalepsy-reducing properties as well. Because muscarinic acetylcholine (mACh) receptor antagonists inhibit the induction of catalepsy, the anticholinergic activities of the drugs were investigated. After SCH23390, nemonapride and scopolamine were administered simultaneously; catalepsy and in vivo mACh receptor occupancy were measured to evaluate quantitatively the anticholinergic activity. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs. Measurement of in vivo mACh receptor occupancy revealed a significant blockade of mACh receptor by all of the tested drugs except for haloperidol. The predicted values of catalepsy, when corrected for the mACh receptor-related reduction, approached the observed values. This finding indicates the possibility that mACh receptor antagonism of drugs may contribute to the reduction of catalepsy. In conclusion, the dynamic model considering D1, D2, and mACh receptor occupancies and synergism between D1 and D2 receptors may be useful for quantitative prediction of drug-induced catalepsy.