Role of Glucuronidation Pathway in Quetiapine Metabolism: An In vivo Drug–Drug Interaction Study between Quetiapine and Probenecid

BACKGROUND: Uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes play a significant role in the metabolism of quetiapine, and coadministration with a UGT inhibitor/inducer drug may change its pharmacokinetic profile. OBJECTIVE: The objective of this study was to assess the impact of probenecid, a UGT enzyme inhibitor, on the pharmacokinetic profile of quetiapine. MATERIALS AND METHODS: Twelve treatment-naïve, 7-week-old male Sprague–Dawley rats (weighting 161 ± 22 g) were randomly and equally divided into control, quetiapine-alone and quetiapine plus probenecid groups. The quetiapine plus probenecid group received a single oral dose of probenecid (50 mg/kg) followed by 50 mg/kg of quetiapine; the quetiapine-alone group only received 50 mg/kg of quetiapine. Blood samples (0.2 ml) were collected from all rats after 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h of the drug administration in heparinized tubes. The pre-established liquid chromatography–mass spectrometry method was utilized to ascertain the plasma concentration of quetiapine and the control group was used to prepare the controlled standard. RESULTS: Significant pharmacokinetic differences were observed between the quetiapine-alone and quetiapine plus probenecid groups in terms of C(max) (392 ± 209 vs. 1323 ± 343 ug/L, respectively, P = 0.004), AUC(0-∞) (P = 0.04) and T(max) (P = 0.004). Further, in the combined drug group, there was a decrease in drug clearance (CL/F) (from 27 ± 11 to 16 ± 3 L/h/kg; P = 0.005) and an increase in the volume of distribution (Vd) (P = 0.01), but there was no significant difference between both groups in terms of half-lives (P = 0.27). No significant within-group variability of pharmacokinetic parameters was observed (P = 0.25). CONCLUSION: The results of this animal study suggest that glucuronidation by UGT enzyme system may also play an important role in quetiapine metabolism, which, if proven in future human studies, would imply that the bioavailability and pharmacokinetic parameters of quetiapine may require alterations when co-administered with probenecid to avoid development of quetiapine toxicity.