5α-Metabolism in Finasteride-Treated Subjects and
Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency

Imperato‐McGinley, Julianne

doi:10.1159/000471751

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…DHT production by male pseudohermaphrodites with inherited 5aR2 deficiency was reported to be 30% of the normal. 16) This is consistent with our result.…”

Section: Discussionsupporting

confidence: 94%

Saturable Binding of Finasteride to Steroid 5α-reductase as Determinant of Nonlinear Pharmacokinetics

Suzuki

Satoh

Ohtani

et al. 2010

Drug Metabolism and Pharmacokinetics

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Finasteride, a steroid 5alpha-reductase (5alphaR) inhibitor, is used to treat benign prostatic hyperplasia and androgenetic alopecia. We aimed to develop a pharmacokinetic/pharmacodynamic model to explain its nonlinear pharmacokinetics and describe the serum concentration profile of dihydrotestosterone (DHT) after finasteride administration. We developed a pharmacokinetic model incorporating a compartment that represents the binding of finasteride to 5alphaR. We fitted this model to the time-concentration profiles of finasteride after repeated administration of finasteride 0.2 and 1 mg/day. We constructed a pharmacodynamic model considering the inhibition of 5alphaR type I and type II (5alphaR1 and 5alphaR2). This model was fitted to the time profiles of serum DHT. The developed pharmacokinetic model well described nonlinear increase in AUC after repeated administration of finasteride. The association and dissociation rate constants were estimated to be 0.0293/nmol/hr and 0.0185/hr, respectively. Pharmacodynamic model analysis suggested that the 5alphaR1 inhibition is dose-dependent in the dose range from 0.2 to 100 mg, while the 5alphaR2 inhibition is almost saturated in the same dose range. Finasteride's saturable binding to 5alphaR2 is the likely cause of its nonlinear pharmacokinetics. The developed pharmacokinetic/pharmacodynamic model should allow prediction of plasma concentration profiles of finasteride and DHT.

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“…DHT production by male pseudohermaphrodites with inherited 5aR2 deficiency was reported to be 30% of the normal. 16) This is consistent with our result.…”

Section: Discussionsupporting

confidence: 94%

Saturable Binding of Finasteride to Steroid 5α-reductase as Determinant of Nonlinear Pharmacokinetics

Suzuki

Satoh

Ohtani

et al. 2010

Drug Metabolism and Pharmacokinetics

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“…It has been proposed that finasteride could impair male sexual development if pregnant women were exposed to this compond. 11 Neither of these children were exposed to this drug during pregnancy.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, the drug finasteride (5‐α‐reductase inhibitor) has been used for the treatment of alopecia and prostate disorders. It has been proposed that finasteride could impair male sexual development if pregnant women were exposed to this compond 11 . Neither of these children were exposed to this drug during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

The child of uncertain sex: 17 years of experience

Al-Agha

Thomsett

Batch

2001

J Paediatrics Child Health

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“…In humans, type I 5AR is present in the skin, liver, adrenal gland, and brain. Type II 5AR is the predominant form in the prostate and skin, is also present in the liver but not in the brain, and is responsible for approximately 70 % of circulating DHT (Imperato-McGinley 1991). Dutasteride has complex elimination kinetics with parallel linear and nonlinear pathways.…”

Section: Resultsmentioning

confidence: 99%

Dutasteride reduces alcohol’s sedative effects in men in a human laboratory setting and reduces drinking in the natural environment

et al. 2014

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Rationale Preclinical studies support the hypothesis that endogenous neuroactive steroids mediate some effects of alcohol. Objectives The aim of this study was to examine the effect of dutasteride inhibition of 5α-reduced neuroactive steroid production on subjective responses to alcohol in adult men. Methods Using a within-subject factorial design, 70 men completed four randomly ordered monthly sessions in which pretreatment with 4 mg dutasteride or placebo was paired with a moderate dose of alcohol (0.8 g/kg) or placebo beverage. The pharmacologic effect of dutasteride was measured by an assay of serum androstanediol glucuronide. Self-reports of alcohol effects were obtained at 40-min intervals following alcohol administration using the Biphasic Alcohol Effects Scale (BAES) and the Alcohol Sensation Scale (SS). We used linear mixed models to examine the effects of dutasteride and alcohol on BAES and SS responses and the interaction of dutasteride with the GABRA2 alcohol dependence-associated polymorphism rs279858. We also examined whether exposure to dutasteride influenced drinking in the weeks following each laboratory session. Results A single 4-mg dose of dutasteride produced a 70 % reduction in androstanediol glucuronide. Dutasteride pretreatment reduced alcohol effects on the BAES sedation and SS anesthesia scales. There was no interaction of dutasteride with rs279858. Heavy drinkers had fewer heavy drinking days during the 2 weeks following the dutasteride sessions and fewer total drinks in the first week after dutasteride. Conclusions These results provide evidence that neuroactive steroids mediate some of the sedative effects of alcohol in adult men and that dutasteride may reduce drinking, presumably through its effects on neuroactive steroid concentrations.

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5α-Metabolism in Finasteride-Treated Subjects and Male Pseudohermaphrodites with Inherited 5α-Reductase Deficiency

Cited by 7 publications

References 14 publications

Saturable Binding of Finasteride to Steroid 5α-reductase as Determinant of Nonlinear Pharmacokinetics

Saturable Binding of Finasteride to Steroid 5α-reductase as Determinant of Nonlinear Pharmacokinetics

The child of uncertain sex: 17 years of experience

Dutasteride reduces alcohol’s sedative effects in men in a human laboratory setting and reduces drinking in the natural environment

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