PMID- 36234746 OWN - NLM STAT- MEDLINE DCOM- 20221017 LR - 20221019 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 27 IP - 19 DP - 2022 Sep 21 TI - Development of UPLC-MS/MS Method to Study the Pharmacokinetic Interaction between Sorafenib and Dapagliflozin in Rats. LID - 10.3390/molecules27196190 [doi] LID - 6190 AB - Sorafenib (SOR), an inhibitor of multiple kinases, is a classic targeted drug for advanced hepatocellular carcinoma (HCC) which often coexists with type 2 diabetes mellitus (T2DM). Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in patients with T2DM. Notably, co-administration of SOR with DAPA is common in clinical settings. Uridine diphosphate-glucuronosyltransferase family 1 member A9 (UGT1A9) is involved in the metabolism of SOR and dapagliflozin (DAPA), and SOR is the inhibitor of UGT1A1 and UGT1A9 (in vitro). Therefore, changes in UGT1A9 activity caused by SOR may lead to pharmacokinetic interactions between the two drugs. The objective of the current study was to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of SOR and DAPA in plasma and to evaluate the effect of the co-administration of SOR and DAPA on their individual pharmacokinetic properties and the mechanism involved. The rats were divided into four groups: SOR (100 mg/kg) alone and co-administered with DAPA (1 mg/kg) for seven days, and DAPA (1 mg/kg) alone and co-administered with SOR (100 mg/kg) for seven days. Liquid-liquid extraction (LLE) was performed for plasma sample preparation, and the chromatographic separation was conducted on Waters XSelect HSS T3 column with a gradient elution of 0.1% formic acid and 5 mM ammonium acetate (Phase A) and acetonitrile (Phase B). The levels of Ugt1a7 messenger RNA (mRNA) were determined in rat liver and intestine using quantitative real-time polymerase chain reaction (qRT-PCR). The method was successfully applied to the study of pharmacokinetic interactions. DAPA caused a significant decrease in the maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC(0-t)) of SOR by 41.6% and 50.5%, respectively, while the apparent volume of distribution (V(z/F)) and apparent clearance (CL(z/F)) significantly increased 2.85- and 1.98-fold, respectively. When co-administering DAPA with SOR, the AUC(0-t) and the elimination half-life (t(1/2Z)) of DAPA significantly increased 1.66- and 1.80-fold, respectively, whereas the CL(z/F) significantly decreased by 40%. Results from qRT-PCR showed that, compared with control, seven days of SOR pretreatment decreased Ugt1a7 expression in both liver and intestine tissue. In contrast, seven days of DAPA pretreatment decreased Ugt1a7 expression only in liver tissue. Therefore, pharmacokinetic interactions exist between long-term use of SOR with DAPA, and UGT1A9 may be the targets mediating the interaction. Active surveillance for the treatment outcomes and adverse reactions are required. FAU - He, Xueru AU - He X AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Graduate School, Hebei Medical University, Shijiazhuang 050011, China. FAU - Li, Ying AU - Li Y AUID- ORCID: 0000-0002-7651-6543 AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050011, China. FAU - Ma, Yinling AU - Ma Y AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050011, China. FAU - Fu, Yuhao AU - Fu Y AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Graduate School, Hebei Medical University, Shijiazhuang 050011, China. FAU - Xun, Xuejiao AU - Xun X AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Graduate School, Hebei Medical University, Shijiazhuang 050011, China. FAU - Cui, Yanjun AU - Cui Y AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Graduate School, Hebei Medical University, Shijiazhuang 050011, China. FAU - Dong, Zhanjun AU - Dong Z AD - National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China. AD - Department of Pharmacy, Hebei General Hospital, Shijiazhuang 050011, China. LA - eng PT - Journal Article DEP - 20220921 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - 0 (Acetonitriles) RN - 0 (Benzhydryl Compounds) RN - 0 (Glucosides) RN - 0 (RNA, Messenger) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 1ULL0QJ8UC (dapagliflozin) RN - 58-98-0 (Uridine Diphosphate) RN - 9NEZ333N27 (Sodium) RN - 9ZOQ3TZI87 (Sorafenib) RN - EC 2.4.1.17 (Glucuronosyltransferase) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Acetonitriles MH - Animals MH - Benzhydryl Compounds MH - *Carcinoma, Hepatocellular/drug therapy MH - Chromatography, High Pressure Liquid/methods MH - Chromatography, Liquid/methods MH - *Diabetes Mellitus, Type 2 MH - Glucose/therapeutic use MH - Glucosides MH - Glucuronosyltransferase/genetics MH - *Liver Neoplasms MH - RNA, Messenger MH - Rats MH - Reproducibility of Results MH - Sodium MH - *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use MH - Sorafenib/pharmacology MH - Tandem Mass Spectrometry/methods MH - Uridine Diphosphate PMC - PMC9571628 OTO - NOTNLM OT - UPLC-MS/MS OT - dapagliflozin OT - drug-drug interactions OT - pharmacokinetics OT - sorafenib COIS- The authors declare no conflict of interest. EDAT- 2022/10/15 06:00 MHDA- 2022/10/18 06:00 PMCR- 2022/09/21 CRDT- 2022/10/14 02:25 PHST- 2022/08/19 00:00 [received] PHST- 2022/09/18 00:00 [revised] PHST- 2022/09/19 00:00 [accepted] PHST- 2022/10/14 02:25 [entrez] PHST- 2022/10/15 06:00 [pubmed] PHST- 2022/10/18 06:00 [medline] PHST- 2022/09/21 00:00 [pmc-release] AID - molecules27196190 [pii] AID - molecules-27-06190 [pii] AID - 10.3390/molecules27196190 [doi] PST - epublish SO - Molecules. 2022 Sep 21;27(19):6190. doi: 10.3390/molecules27196190.