Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats.

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. Low-molecular-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 ß-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.

Influence of UDP-glucuronosyltransferase polymorphisms on valproic acid pharmacokinetics in Chinese epilepsy patients.

PURPOSE: The aim of this study was to investigate the genetic polymorphisms of UGT1A3, UGT1A6, and UGT2B7 in Chinese epilepsy patients and their potential influence on the pharmacokinetics of valproic acid (VPA). METHODS: The genetic architectures of UGT1A3, UGT1A6, and UGT2B7 in 242 epilepsy patients were detected by DNA sequencing and PCR-restriction fragment length polymorphism. Steady-state plasma concentrations of VPA in 225 patients who had received VPA (approx. 250-1,000 mg/day) for at least 2 weeks were determined and associated with UGT polymorphisms. RESULTS: The allelic distribution of UGT1A3 in our Chinese epilepsy patients was significantly different from that in healthy subjects based on reference data. The standardized trough plasma concentration (C(S)) of VPA was much lower in our patients with the UGT1A3*5 variant than in the wild type carriers (3.24 ± 1.05 vs. 4.68 ± 1.24 µg·kg·mL(-1)·mg(-1), P < 0.01). UGT polymorphisms had no influence on the pharmacokinetic interactions between carbamazepine and VPA. CONCLUSION: 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.

Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine.

OBJECTIVE: Herein we aim to test if pummelo furanocoumarins can inhibit cytochrome P450 (CYP) 3A both in vitro and in vivo, and to explore the influence of CYP3A5*3 (GenBank AC005020: A22893-->G) polymorphism in the pharmacokinetics and pharmacological response to felodipine. METHOD: Fruit juices of pummelo grapefruit (Citrus paradisi Macf., G), 'Guanximiyou' (C. grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C. changshanhuyou Y.B. Chang, H) were selected by screening Citrus fruit juices for their furanocoumarin contents and their inhibition of testosterone 6beta-hydroxylation in human liver microsomes. Twelve healthy male Chinese were administered 250 mL G, P, H or water (W) alternatively with 26-mumol (10-mg) plain tablet felodipine, and were observed for 12 h. RESULTS: G had more furanocoumarins and at higher levels than P while H had none, and their potencies for in vitro CYP3A inhibition were in the order as G > P > H. The geometric mean and 90% confidence intervals of pharmacokinetic parameters for human oral felodipine with G, P, H and W were respectively as follows: peak plasma concentration (nmol.L(-1)), 37 (32-44), 25 (21-29), 19 (16-22) and 18 (15-21); area under the plasma concentration-time curve (nmol.h.L(-1)), 118 (103-136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects showed higher heart rates with G than with H or W. CYP3A5*3 polymorphism showed no significant effect on felodipine pharmacokinetics and related hemodynamic changes. CONCLUSIONS: This work supports the hypothesis that CYP3A inhibition by furanocoumarins caused pummelo fruit juice-drug interaction; while the role of CYP3A5 in the population pharmacokinetics of felodipine and blood pressure response appear to be limited.

Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients.

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.