Our results suggest that UGT1A3*5 may be an important determinant of individual variability in the pharmacokinetics of VPA and that it may be necessary to increase VPA dose for UGT1A3*5 carriers to ensure its therapeutic range of 50-100 μg/mL.

Aim: To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. Methods: The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR‐ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose‐adjusted trough concentrations and metabolic ratio (MR) values were calculated. Results: The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1 *3). However, no significant difference was found for the dose‐adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92±0.62 for CYP3A5*3/*3 (n=14), 0.99±0.51 for CYP3A5*1/*3 (n=15), and 1.45±0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. Conclusion: The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites.

Aim: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Methods: Male SD rats were orally administered VPA (100 or 500 mg·kg -1 ·d -1 ) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Lowmolecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.