title: Investigation of Drug-Drug Interactions Between Ritobegron, a Selective β3 -Adrenoceptor Agonist, With Probenecid in Healthy Men.
abstract: We evaluated the effects of probenecid, a potent organic anion transporter 1 (OAT1) and OAT3 inhibitor, on the pharmacokinetics and safety of ritobegron, a selective β3 -adrenoceptor agonist, in healthy men. Twelve healthy men were administered a single oral dose of ritobegron (20 mg) alone or in combination with probenecid 2 hours before administration of ritobegron. In the combination sequence, additional doses of probenecid were administered 4 and 10 hours after the administration of ritobegron. Probenecid increased the Cmax of KUC-7322, an active form of ritobegron, and the AUC0-48  h by 1.39 and 2.93 times, respectively. Probenecid prolonged the t1/2 of KUC-7322 from 1.6 to 3.4 hours and decreased the renal clearance and cumulative fraction of KUC-7322 excreted in urine from 18.5 to 4.9 L/h and from 64.7% to 49.7%, respectively. Coadministration of probenecid did not influence adverse events, blood pressure, pulse rate, or heart rate relative to ritobegron alone. Although probenecid inhibited renal tubule secretion of KUC-7322 via OAT3 and increased KUC-7322 exposure, it did not influence adverse effects or vital signs. Therefore, clinically significant drug-drug interactions are unlikely to occur when probenecid is administered in combination with OAT3 inhibitors or substrates.
authors.affiliation: Pharmacokinetics Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Clinical Development Planning & Management Dept., Kissei Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Toxicological Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kanazawa
authors.affiliation: Clinical Development Planning & Management Dept., Kissei Pharmaceutical Co., Ltd., Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Furihata
authors.affiliation: Pharmacokinetics Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Endo
authors.affiliation: Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000085:Acetates / Q000009:adverse effects / Q000493:pharmacokinetics*; D058667:Adrenergic beta-3 Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology*; D055815:Young Adult; D010136:p-Hydroxyamphetamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000085:Acetates; D058667:Adrenergic beta-3 Receptor Agonists; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D010136:p-Hydroxyamphetamine; C576374:ritobegron; D011339:Probenecid
keywords: drug interactions; organic anion transporter 3 inhibitor; probenecid; ritobegron; β3-adrenoceptor agonist