Skip to Content
Merck
  • Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.

Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.

Die Pharmazie (2015-05-16)
Y Abe, E Ota, H Harada, H Kanbe, Y Kojima, T Kanazawa, T Endo, M Murakami, M Kobayashi
ABSTRACT

Ritobegron, a selective β3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
HEPES, BioUltra, for molecular biology, ≥99.5% (T)
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, for protein sequence analysis, ampule, ≥99.5% (GC)
Pricing and availability is not currently available.
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥99.0% (T)
Pricing and availability is not currently available.
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥98.5% (GC)
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, ≥99%
Pricing and availability is not currently available.
Sigma-Aldrich
HEPES, BioXtra, suitable for mouse embryo cell culture, ≥99.5% (titration)
Pricing and availability is not currently available.
Sigma-Aldrich
HEPES, BioXtra, pH 5.0-6.5 (1 M in H2O), ≥99.5% (titration)
Pricing and availability is not currently available.
Sigma-Aldrich
Nifedipine, ≥98% (HPLC), powder
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, ≥99.5%
Pricing and availability is not currently available.
Sigma-Aldrich
Coumarin, ≥99% (HPLC)
Pricing and availability is not currently available.
Coumarin, primary reference standard
Pricing and availability is not currently available.
Sigma-Aldrich
Estrone, ≥99%
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, puriss. p.a., ≥99.5% (GC)
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, for amino acid analysis, ≥99.5% (GC)
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, BioUltra, ≥99.5% (GC)
Pricing and availability is not currently available.
SAFC
HEPES
Pricing and availability is not currently available.
Supelco
Nifedipine, Pharmaceutical Secondary Standard; Certified Reference Material
Pricing and availability is not currently available.
Supelco
Coumarin, certified reference material, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Pricing and availability is not currently available.
Estrone, European Pharmacopoeia (EP) Reference Standard
Pricing and availability is not currently available.
Supelco
HEPES, Pharmaceutical Secondary Standard; Certified Reference Material
Pricing and availability is not currently available.
Sigma-Aldrich
HEPES, anhydrous, free-flowing, Redi-Dri, ≥99.5%
Pricing and availability is not currently available.
Nifedipine, European Pharmacopoeia (EP) Reference Standard
Pricing and availability is not currently available.
USP
Nifedipine, United States Pharmacopeia (USP) Reference Standard
Pricing and availability is not currently available.
Coumarin, European Pharmacopoeia (EP) Reference Standard
Pricing and availability is not currently available.
Supelco
Estrone, Pharmaceutical Secondary Standard; Certified Reference Material
Pricing and availability is not currently available.
USP
Estrone, United States Pharmacopeia (USP) Reference Standard
Pricing and availability is not currently available.
SAFC
HEPES
Pricing and availability is not currently available.
Supelco
Triethylamine, analytical standard
Pricing and availability is not currently available.
Sigma-Aldrich
Triethylamine, ≥99.5%
Pricing and availability is not currently available.
Sigma-Aldrich
Bicinchoninic acid disodium salt hydrate, ≥98% (HPLC)
Pricing and availability is not currently available.