Identification of Uridine 5′-Diphosphate-Glucuronosyltransferases Responsible for the Glucuronidation of Mirabegron, a Potent and Selective β3-Adrenoceptor Agonist, in Human Liver Microsomes

Konishi, Kentaro; Tenmizu, Daisuke; Takusagawa, Shin

doi:10.1007/s13318-017-0450-x

Cited by 6 publications

(2 citation statements)

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“…Pivotal phase 3 trials showed that a single daily oral administration of mirabegron (25 and 50 mg) is an effective treatment for overactive bladder with a favorable safety profile as demonstrated by a low incidence of treatment‐emergent adverse events (Herschorn et al, ; Khullar et al, ; Nitti et al, ; Yamaguchi et al, ). Thus far, CYP3A4, UGT2B7 and BChE, and renal excretion are the only identified major elimination pathways for mirabegron (Konishi, Tenmizu, & Takusagawa, ; Krauwinkel et al, ; Takusagawa et al, ).…”

Section: Introductionmentioning

confidence: 99%

Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment

Konishi

Minematsu

Nagasaka

et al. 2019

Biopharm & Drug Disp

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We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi‐elimination pathway mediated by CYP3A4, uridine 5′‐diphosphate‐glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug–drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta‐analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration–time profile for mirabegron in an sRI population (simulated area under the plasma concentration–time curve (AUC) was within 1.5‐times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12‐times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.

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Section: Introductionmentioning

confidence: 99%

Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment

Konishi

Minematsu

Nagasaka

et al. 2019

Biopharm & Drug Disp

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“…O MBG realiza ligação às proteínas plasmáticas no intervalo de 71% a 77% e é metabolizado por vias como, a hidrólise de amida, glucuronidação, N-desalquilação e oxidação 213 e enzimas tais como, butirilcolinesterase, UDP-glucuronosiltransferases 214 , e possivelmente álcool desidrogenase 215 .…”

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Mirabegron preserva o efeito hipocontrátil do PVAT aórtico durante a obesidade

Bressan

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Physiologically-Based Pharmacokinetic Models of CYP2D6 Substrate and Inhibitors Nebivolol, Cinacalcet and Mirabegron to Simulate Drug–Drug Interactions

Kilford

Khoshaein

Southall

et al. 2022

Eur J Drug Metab Pharmacokinet

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Identification of Uridine 5′-Diphosphate-Glucuronosyltransferases Responsible for the Glucuronidation of Mirabegron, a Potent and Selective β3-Adrenoceptor Agonist, in Human Liver Microsomes

Abstract: UGT2B7 is the main catalyst of M11 formation in HLMs. Regarding M13 and M14 formation, UGT1A3 and UGT1A8 are strong candidates for glucuronidation, respectively.

Cited by 6 publications

References 24 publications

Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment

Application of a physiologically based pharmacokinetic model for the prediction of mirabegron plasma concentrations in a population with severe renal impairment

Mirabegron preserva o efeito hipocontrátil do PVAT aórtico durante a obesidade

Physiologically-Based Pharmacokinetic Models of CYP2D6 Substrate and Inhibitors Nebivolol, Cinacalcet and Mirabegron to Simulate Drug–Drug Interactions

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