Pharmacokinetics and biochemical efficacy after single and multiple oral administration of N-(2-methyl-2-propyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, a new type of specific competitive inhibitor of testosterone 5α-reductase, in volunteers

Ohtawa, Masakatsu; Morikawa, Hajime; Shimazaki, Jun

doi:10.1007/bf03189869

Cited by 57 publications

(30 citation statements)

References 11 publications

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“…To maximize the antagonism of 5AR activity (Ohtawa et al, 1991), subjects received either finasteride 100 mg or placebo in identical capsules 24 h prior to each laboratory session (see Figure 1) and were instructed to avoid alcohol, nicotine, or other drugs (except caffeine) until after completion of the laboratory session. Subjects arrived at the laboratory at 0800, having been instructed to fast from solid foods for 8 h prior to the session.…”

Section: Laboratory Proceduresmentioning

confidence: 99%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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GABA A receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABA A receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABA A receptor a-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-a steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n ¼ 7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n ¼ 20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

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Section: Laboratory Proceduresmentioning

confidence: 99%

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

Pierucci‐Lagha

Covault

Feinn

et al. 2005

Neuropsychopharmacol

133

109

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“…This effect can remain for five to seven days 12 . After 14 days of treatment discontinuity the levels of finasteride returned to baseline 12,13 . In this investigation the experimental animals were administered finasteride three times per week.…”

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confidence: 91%

The effect of finasteride on spermatogenesis of Mesocricetus auratus

et al. 2008

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RESUMOObjetivo: Estudar o impacto da finasterida na espermatogênese do Mesocricetus auratus, adulto. Métodos: Foram avaliados 20 hamsters adultos, com idades superiores a 1 ano, distribuídos em dois grupos: grupo controle com dez animais (n=10) e grupo experimental também com dez animais (n=10). No grupo experimental foi aplicado 7,14ng/mL (0,5mL) de finasterida por 100mg/Kg/peso, subcutâneo (SC), na região dorsal do animal, três vezes por semana por 90 dias, dose correspondente a 5mg da droga usada em homens adultos, para tratamento da hiperplasia benigna da próstata (HBP). No final de três meses, esses Hamsters foram mortos por hipovolemia, após serem anestesiados com cloridrato de quetamina, na dosagem de 200 mg/kg juntamente com diazepam, na dosagem de 2,5 mg/kg. Os testículos foram retirados em monobloco juntamente com todo o aparelho geniturinário, fixados em formalina a 10% e encaminhados à histotécnica para posterior análise histológica em microscópico óptico. Foram usadas para coloração das lâminas a hematoxilina e eosina (HE). Resultados: Quando foram mortos, os Hamsters do grupo de controle pesaram em média 129,0g e desvio padrão (DP) de 18,8g. O grupo de experimento apresentou média de peso de 145,0g e DP de 15,25g. A idade dos animas de controle quando foram mortos apresentou média de 15,2 meses e DP de 1,13 meses. Os animais de experimento apresentaram média de idade de 17,16 meses e DP de 0,82. A diferença das médias de peso entre os dois grupos não teve significado estatístico (p=0,0514). Os animais (100%) do grupo controle não tiveram alterações tubulares e apresentaram todas as etapas da espermatogênese normais. Quatro animais (40%) do grupo de experimento apresentaram hipotrofia dos túbulos seminíferos, e seis (60%) desses animais apresentaram espermatogênese normal, mas diminuída em relação ao grupo controle. Do ponto de vista estatístico houve significância (p=0,043) entre o grupo de experimento e controle em relação às alterações testiculares. Conclusão: Os animais em uso de finasterida apresentaram atrofia tubulares significativas e diminuição da espermatogênese em comparação com o grupo-controle. Descritores: Mesocricetus. Finasterida, Testículo. Espermatogênese. ABSTRACT Purpose:To study the effect of finasteride on the spermatogenesis of adult Mesocricetus auratus. Methods: Twenty adult hamsters were evaluated. The animals were one year-older, and were randomly divided in 2 different groups: control group with ten animals (n=10) and experimental group also with ten animals (n=10). The animals in the experimental group were shot 7.14 ng/mL (0.5mL) of finasteride by 100mg/Kg, subcutaneously in the dorsal region three times per week during 90 days. This dose correspondes to 5mg of the drug used in adult men for the treatment of benign prostatic hyperplasia (BPH). After three months, the animals were anesthetized through association of 200mg/kg ketamine chloridrate and 2.5 mg/kg of diazepan and were dead through hypovolemia.. The testis removed along with the whole genitourinary apparel wer...

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“…Today, there is no information on the safety aspects of this finding. Finasteride has a terminal half-life of ϳ5 h in humans, but its pharmacodynamic effect lasts up to 72 h (Ohtawa et al, 1991). Contribution of an active metabolite with a long half-life could explain this observation.…”

mentioning

confidence: 99%

Identification of Finasteride Metabolites in Human Bile and Urine by High-Performance Liquid Chromatography/Tandem Mass Spectrometry

Lundahl¹,

Lennernäs²,

Knutson³

et al. 2009

Drug Metab Dispos

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ABSTRACT:The objective of this study was to further investigate the metabolism of the 5␣-reductase inhibitor, finasteride, and to identify previously unknown phase I and phase II metabolites in vitro and in vivo in human bile and urine. Healthy volunteers were given 5 mg of finasteride, directly to the intestine, and bile and urine were collected for 3 and 24 h, respectively. A single-pass perfusion technique, Loc-I-Gut, was used for drug administration and bile collection from the proximal jejunum, distal to papilla of Vater. Incubations with human liver microsomes/S9 fractions and different cofactors were performed with finasteride and the previously known metabolites, -hydroxy finasteride (M1) and finasteride--oic acid (M3). Liquid chromatography coupled to triple quadrupole mass spectrometry (MS) with positive/negative electrospray ionization and ion trap with MS n measurements were used for structural investigations and identification of metabolites. Two hydroxy metabolites of finasteride, other than M1, and one intact hydroxy finasteride glucuronide were identified in vitro and in bile and urine. The glucuronide and at least one of the hydroxy metabolites were previously unidentified. M1 and M3 were glucuronidated in vitro by specific human UDP-glucuronosyltransferases, UGT1A4 and UGT1A3, respectively. M1 glucuronide was not identified in vivo, and M3 glucuronide, an acyl glucuronide, was present in low amounts in bile from a few individuals. In conclusion, previously undescribed metabolites were identified, in vitro and in human urine and bile. Bile collection using the Loc-I-Gut technique followed by sensitive mass spectrometry analysis led to the discovery of novel, both phase I and phase II, finasteride metabolites in human bile.

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Pharmacokinetics and biochemical efficacy after single and multiple oral administration of N-(2-methyl-2-propyl)-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, a new type of specific competitive inhibitor of testosterone 5α-reductase, in volunteers

Cited by 57 publications

References 11 publications

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

The effect of finasteride on spermatogenesis of Mesocricetus auratus

Identification of Finasteride Metabolites in Human Bile and Urine by High-Performance Liquid Chromatography/Tandem Mass Spectrometry

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