Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

Abstract

Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.

Simultaneous Detection of 14 Microcystin Congeners from Tissue Samples Using UPLC- ESI-MS/MS and Two Different Deuterated Synthetic Microcystins as Internal Standards

“…Differences in binding affinity of MC-LF and-LR for the murine organic anion polypeptide transporter mOatp1b2 have been observed [37,38]. Interestingly, females tended to show lower detectable amounts of MC-LF in both matrices than males, an observation that could stem from a sex-dependent expression levels of Oatp1b2 which is hormonally regulated, as observed for other murine Oatps [44,51]. However, the latter findings need to be taken with caution, as only two replicates were used.…”

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake

“…When bile is secreted into the gut after food intake, 17 regorafenib is reabsorbed, potentially accounting for prolonged plasma exposure. 18 of regorafenib, with women having a lower CL P than men. The final model suggests that an increase in BMI leads to a decrease in CL P ; this may be a result of lower CYP3A4 expression, resulting in lower CL P of CYP3A4 substrates, which has been reported in patients with high BMI.…”

“…When bile is secreted into the gut through gallbladder emptying after food intake, 17 regorafenib and its metabolites may be reabsorbed. 18 Therefore, the comprehensive population PK model for regorafenib and its metabolites described here incorporates EHC.…”

Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases

“…In the US and Europe, it is most often designated for patients with mCRC who have failed previous therapies or who are not candidates for other approaches. Although regorafenib is an effective antineoplastic compound, diarrhea is one of the most frequently observed adverse reactions. − Regorafenib and its close structural homologue sorafenib, which is used for kidney, liver, and thyroid cancer (and also causes diarrhea), are known to be glucuronidated in mice, rats, and humans and to reach the GI tract as inactivated glucuronide metabolites. − Thus, one mechanism by which regorafenib may cause GI toxicity is the reactivation of the drug within the GI lumen by gut microbial β-glucuronidase enzymes. − …”