Investigation of Drug-Drug Interactions Between Ritobegron, a Selective ß3 -Adrenoceptor Agonist, With Probenecid in Healthy Men.

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 ß3 -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.

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

Ritobegron, a selective ß3-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.

Absorption, disposition, metabolism, and excretion of ritobegron (KUC-7483), a novel selective ß3-adrenoceptor agonist, in rats.

The pharmacokinetic profile of ritobegron, a novel, selective ß3-adrenoceptor agonist, was investigated in rats. Ritobegron, an ethyl ester prodrug of the active compound KUC-7322, or KUC-7322 itself was orally administered (10 mg/kg). Ethyl esterification resulted in a 10-fold increase in the area under the plasma concentration-time curve (AUC(0-t)), as compared to KUC-7322. Following intravenous administration of KUC-7322 (1 mg/kg), total blood clearance was 1.36 L/h/kg, suggesting that intrinsic hepatic clearance is the rate-limiting step in KUC-7322 excretion. When ritobegron was orally administered (0.3, 1, 3, and 10 mg/kg), plasma concentrations of KUC-7322 rapidly increased and reached a maximum concentration (C(max)) at 0.25 to 0.31 h. KUC-7322 levels rapidly decreased, with a half-life (t 1/2) of 0.42 to 1.37 h thereafter. AUC(0-t) did not show a dose-dependent increase. The bioavailability of KUC-7322 was estimated to be 4%. Following oral administration of [14C]ritobegron (3 mg/kg), radioactivity concentrations in tissues rapidly increased and declined in parallel with changes in plasma concentration. In most of tissues, excluding the liver, kidney, urinary bladder, stomach and small intestine, radioactivity concentrations were lower than that in plasma. In plasma, bile, urine, and feces, KUC-7322 and its glucuronide, sulfate, and glutathione conjugates were detected. The glucuronide conjugate of KUC-7322 was the predominant metabolite in bile, plasma, and urine, and KUC-7322 was predominant in feces. Ritobegron was not detected in any of the samples. The cumulative excretion of radioactivity in urine and feces were 28.7% and 68.3% of the dose, respectively, up to 120 h after administration.

Simultaneous HPLC analysis of optical isomers of methamphetamine and its metabolites, and stereoselective metabolism of racemic methamphetamine in rat urine.

Simultaneous identification of optical isomers (D and L) of methamphetamine (MAMP), amphetamine (AMP), para(p)-hydroxy(OH)-MAMP, and para(p)-hydroxy(OH)-AMP in rat urine was attempted by high-performance liquid chromatography (HPLC). They were determined as benzoyl derivatives. After administration of D- or L-isomer (15 mg/kg), only D- or L-isomers of the above mentioned metabolites were found in rat urine. In rats administered racemic MAMP (15 mg/kg), each percent dose of L-isomers of MAMP or AMP excreted at four collection times up to 24 h was less than that of the D-isomer (L/D less than 1.00), but the doses of L-isomers of p-OH-MAMP and p-OH-AMP excreted were higher than those of D-isomers (L/D greater than 1.00). Simultaneous analysis within 36 minutes showed good peak resolution. The L/D ratio for each metabolite decreased with time. The total percent doses of D- or L-isomer excreted by 24 hours were about 50% of the administered dose, 23.70 +/- 1.45% for the D-isomer, 25.70 +/- 1.54% for the L-isomers. The total L/D ratio was 1.08 +/- 0.03. These results indicated that Wistar rats have no chiral isomerization enzyme of MAMP, and show stereoselective metabolism of DL-MAMP. In the optical isomer analysis of 11 MAMP powder samples and 28 human urine specimens obtained from Japanese abusers, only D-MAMP was detected in the powder, and D-MAMP and D-AMP were detected in urine, respectively. This suggested that humans have no chiral isomerization enzyme of D-MAMP.