title: Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.
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.
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: E
authors.initials: E
authors.lastname: Ota
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: H
authors.initials: H
authors.lastname: Kanbe
authors.forename: Y
authors.initials: Y
authors.lastname: Kojima
authors.forename: T
authors.initials: T
authors.lastname: Kanazawa
authors.forename: T
authors.initials: T
authors.lastname: Endo
authors.forename: M
authors.initials: M
authors.lastname: Murakami
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics* / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D013045:Species Specificity; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010136:p-Hydroxyamphetamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000085:Acetates; D058667:Adrenergic beta-3 Receptor Agonists; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D010136:p-Hydroxyamphetamine; C576374:ritobegron