Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology.

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.

Comparison of different bridging anticoagulation therapies used after mechanical heart valve replacement in Chinese patients - a prospective cohort study.

OBJECTIVE: To assess different bridging anticoagulation therapies early after mechanical heart valve replacement (MHVR) in Chinese patients. METHODS: We performed a prospective, single-center, observational cohort study of 305 patients who underwent elective MHVR with different bridging anticoagulation regimens. Patients enrolled in the study were divided into three bridging therapy groups: the unfractionated heparin (UFH) group (n = 109), the low-molecular-weight heparin (LMWH) group (n = 97), and the UFH with sequential LMWH (UFH-LMWH) group (n = 99). All patients were followed for 4 weeks. RESULTS: Two patients experienced thromboembolic stroke events in the UFH group. The LMWH group was associated with an increase in the incidence of bleeding events compared with the UFH group (10.3% VS 2.8%; P = 0.03). With a comparison of LMWH and UFH group in secondary endpoints, the statistical test for significance indicated a trend of reduced ICU length of stay (P = 0.08), postoperative length of stay (P = 0.08) and time of achieving target INR (P = 0.06). The creatinine level (odds ratio = 1.03; 95% confidence interval = 1.01 to 1.05; P = 0.02) and hypertension (odds ratio = 3.72; 95% confidence interval = 1.35 to 10.28; P = 0.01) were risk factors for bleeding events. CONCLUSION: For Chinese patients, the LMWH bridging anticoagulation presents the increased the incidence of bleeding events, but enables patients to benefit from achieving an early anticoagulation effect. Close follow-up and personalized management are required in patients with thromboembolic and bleeding risk factors. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800019841. Registered 2 December 2018 retrospectively.

[Effects of Yuquan pills on pharmacokinetics of metformin hydrochloride in diabetic rats].

OBJECTIVE: To study effects of Yuquan pills on the pharmacokinetics process of metformin hydrochloride in diabetic rats. METHOD: After administration Yuquan pills 7 day to the diabetic rats, the metformin hydrochloride was orally administrated, then the blood samples were collected at different time. The concentrations of metformin hydrochloride in plasma were determined by HPLC method and the pharmacokinetic parameters were calculated. RESULT: The pharmacokinetic parameter Cmax of the controlling group and the testing group were respectively, 18.95, 21.76 mg x L(-1); t1/2 were 1,069.8, 1,767.4 min, respectively; CL/F were 0.013, 0.008 L x min(-1) x kg(-1); AUC were 10,042.1, 10,712.2 mg z L(-1) x min(-1) respectively. CONCLUSION: The pharmacokinetics process of metformin hydrochloride in diabetic rats fits one-compartment model. Yuquan pills has a significant effect on the pharmacokinetics of metformin hydrochloride in diabetic rats.