[PMID]: | 27695293 |
[Au] Autor: | Min JS; Kim D; Park JB; Heo H; Bae SH; Seo JH; Oh E; Bae SK |
[Ad] Endereço: | Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon. |
[Ti] Título: | Application of physiologically based pharmacokinetic modeling in predicting drug-drug interactions for sarpogrelate hydrochloride in humans. |
[So] Source: | Drug Des Devel Ther;10:2959-2972, 2016. |
[Is] ISSN: | 1177-8881 |
[Cp] País de publicação: | New Zealand |
[La] Idioma: | eng |
[Ab] Resumo: | BACKGROUND: Evaluating the potential risk of metabolic drug-drug interactions (DDIs) is clinically important. OBJECTIVE: To develop a physiologically based pharmacokinetic (PBPK) model for sarpogrelate hydrochloride and its active metabolite, ( )-1-{2-[2-(3-methoxyphenyl)ethyl]-phenoxy}-3-(dimethylamino)-2-propanol (M-1), in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP) 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. METHODS: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. RESULTS: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol, desipramine, imipramine, dextromethorphan, and tolterodine following single and multiple sarpogrelate hydrochloride oral doses were within the range of ≥1.25, but <2-fold, indicating that sarpogrelate hydrochloride is a weak inhibitor of CYP2D6 in vivo. Collectively, the predicted low DDIs suggest that sarpogrelate hydrochloride has limited potential for causing significant DDIs associated with CYP2D6 inhibition. CONCLUSION: This study demonstrated the feasibility of applying the PBPK approach to predicting the DDI potential between sarpogrelate hydrochloride and drugs metabolized by CYP2D6. Therefore, it would be beneficial in designing and optimizing clinical DDI studies using sarpogrelate as an in vivo CYP2D6 inhibitor. |
[Mh] Termos MeSH primário: |
Citocromo P-450 CYP2D6/química Dimetilaminas/farmacocinética Propanóis/farmacocinética Succinatos/farmacocinética
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[Mh] Termos MeSH secundário: |
Simulação por Computador Citocromo P-450 CYP2D6/metabolismo Dimetilaminas/química Dimetilaminas/metabolismo Interações Medicamentosas Seres Humanos Modelos Biológicos Propanóis/química Propanóis/metabolismo Succinatos/química Succinatos/metabolismo
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 ((R,S)-1-(2-(2-(3-methoxyphenyl)ethyl)-phenoxy)-3-(dimethylamino)-2-propanol); 0 (Dimethylamines); 0 (Propanols); 0 (Succinates); 19P708E787 (sarpogrelate); EC 1.14.14.1 (Cytochrome P-450 CYP2D6) |
[Em] Mês de entrada: | 1704 |
[Cu] Atualização por classe: | 170405 |
[Lr] Data última revisão:
| 170405 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 161004 |
[St] Status: | MEDLINE |
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