Pharmacokinetic and pharmacodynamic study of a new nonsteroidal 5 alpha-reductase inhibitor, 4-[3-[3-[Bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl]-butyr ic acid, in rats.

The pharmacokinetic and pharmacodynamic behaviors of 4-[3-[3-[Bis(4-isobutylphenyl) methylamino] benzoyl]-1H-indol-1-yl]-butyric acid (FK143), a new nonsteroidal steroid 5 alpha-reductase inhibitor, in the ventral prostate were investigated after i.v. administration to rats. The relationship between blood concentrations at 24 hr and doses was linear in the range of 0.1 to 20 mg/kg. However, the levels of FK143 in the prostate were saturated over the dose of over 5 mg/kg. The dissociation constant (Kd) and maximum amount of binding substances (Bmax), calculated according to nonlinear kinetic analysis including a specific binding pool, was 0.0553 +/- 0.0117 microgram/ml (92 nM, estimated value +/- S.D.) and 0.908 +/- 0.092 microgram/g tissue, respectively. A combined pharmacokinetic/pharmacodynamic (PK/PD) model was constructed using change in dihydrotestosterone (DHT) levels in the prostate after i.v. administration of FK143 as an index for its pharmacological effect and blood concentration as an input function. The apparent reaction rate constant of drug and enzyme (K) was 39.7 +/- 25.1 g tissue/microgram/hr (estimated value +/- S.D.), the apparent turn-over rate constant of enzyme (k) was 0.140 +/- 0.107 hr-1, the elimination rate constant of DHT (kel, DHT) was 1.13 +/- 0.94 hr-1 and the fraction of FK143-insensitive DHT synthesis (F) was 0.461 +/- 0.037. The PK/PD analysis suggested that the duration of the effect of FK143 was related to its accumulation in the binding pool of the prostate. After i.v. administration of FK143 in the range of 0.1 to 20 mg/kg, the DHT levels in the prostate decreased to about 40% of control value, after which despite the rapid decline of blood FK143 concentration, slowly recovered according to the elimination rate of FK143 in the prostate. Moreover, the PK/PD profiles of FK143 after repeated i.v. administration were predictable by using the PK/PD parameters obtained after single administration of FK143.

[1]  D. Peters,et al.  Finasteride , 1993, Drugs.

[2]  N. Bruchovsky,et al.  The intranuclear binding of testosterone and 5-alpha-androstan-17-beta-ol-3-one by rat prostate. , 1968, The Journal of biological chemistry.

[3]  G. Hammond.  Endogenous steroid levels in the human prostate from birth to old age: a comparison of normal and diseased tissues. , 1978, The Journal of endocrinology.

[4]  A. Sandberg.  Endocrine control and physiology of the prostate , 1980, The Prostate.

[5]  H. Yamanaka,et al.  Inhibition of 3α‐hydroxysteroid oxidoreductase and 5α‐reductase activity by antiandrogens and indomethacin in the rat prostate , 1992 .

[6]  J. Wilson,et al.  Dihydrotestosterone in prostatic hypertrophy. II. The formation and content of dihydrotestosterone in the hypertrophic canine prostate and the effect of dihydrotestosterone on prostate growth in the dog. , 1970, The Journal of clinical investigation.

[7]  H. Thijssen,et al.  Target-based warfarin pharmacokinetics in the rat: the link with the anticoagulant effect. , 1994, The Journal of pharmacology and experimental therapeutics.

[8]  M. Katashima,et al.  Comparative pharmacokinetic/pharmacodynamic study of proton pump inhibitors, omeprazole and lansoprazole in rats. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[9]  G. Andriole,et al.  The effect of finasteride in men with benign prostatic hyperplasia. , 1992, The Journal of urology.

[10]  J. Abalain,et al.  Metabolism of androgens in human hyperplastic prostate: evidence for a differential localization of the enzymes involved in the metabolism. , 1989, Journal of steroid biochemistry.

[11]  W. Owens,et al.  Studies of the nuclear 5 alpha-reductase of human prostatic tissue: comparison of enzyme activities in hyperplastic, malignant, and normal tissues. , 1983, Canadian journal of biochemistry and cell biology = Revue canadienne de biochimie et biologie cellulaire.

[12]  D. S. Coffey,et al.  Changes in dihydrotestosterone metabolism associated with the development of canine benign prostatic hyperplasia. , 1981, Endocrinology.

[13]  M. Okuhara,et al.  FK143, a novel nonsteroidal inhibitor of steroid 5α-reductase: (1) In vitro effects on human and animal prostatic enzymes , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  J. Wilson,et al.  Dihydrotestosterone in prostatic hypertrophy. I. The formation and content of dihydrotestosterone in the hypertrophic prostate of man. , 1970, The Journal of clinical investigation.

[15]  S. Liao,et al.  Selective Retention of Dihydrotestosterone by Prostatic Nuclei , 1968, Nature.

[16]  J F Steiner,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Finasteride , 1996, Clinical pharmacokinetics.

[17]  Koujirou Yamamoto,et al.  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 , 1997 .

[18]  S. Ostrove,et al.  Binding of a 4-methyl-4-aza-steroid to 5 alpha-reductase of rat liver and prostate microsomes. , 1983, Endocrinology.

[19]  Yasuhiko Yamada,et al.  Parmacodynamic Analysis of Antiplatelet Effect of Aspirin in the Literature. Modeling Based on Inhibition of Cyclooxygenase in the Platelet and the Vessel Wall Endothelium. , 1996 .

[20]  J. Gustafsson,et al.  Isolation of mitochondria, lysosomes, and microsomes from the rat ventral prostate with a note on inverted microsomal vesicles. , 1983, Archives of biochemistry and biophysics.