Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder.

PURPOSE: To develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population. METHODS: A total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model. RESULTS: A one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70 kg administered VPA 1000 mg/day were 0.18 h-1, 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model. CONCLUSIONS: A qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients.

Adverse effects in Daphnia magna exposed to e-waste leachate: Assessment based on life trait changes and responses of detoxification-related genes.

The sharp increase in e-waste derived from great consumption of electronic products has become a potential global environmental challenge. Limited information is available about the potential detrimental impact of e-waste on aquatic organisms. The present study investigated the expression of detoxification-related genes and life-history parameter changes in Daphnia magna exposed to e-waste leachate, simultaneously integrating with the chemical analysis of typical pollutants from e-waste leachate. The study aims at assessing impacts of e-waste to aquatic invertebrates and providing insights into its toxic mechanisms. The results showed high concentration of heavy metals like Cu (1657.14 ± 259.3 µg g-1, DW) and persistent organic compounds like polybrominated diphenyl ethers (7831.32 ± 1273.86 ng g-1, DW) in stream sediments near e-waste dismantling areas. Chronic exposure to these pollutants can affect the growth and reproduction of D. magna, resulting in significant development retardation, decreased total egg production per female, and even smaller body size. Expression of some detoxification and reproduction-related genes including DappuHR96, CYP360a, P-gp, EcR, CYP314 and Vtg exhibited different response patterns depending on the e-waste leachate concentration. E-waste leachate may affect the expression of detoxification-related and growth and reproduction-related genes and disrupt the growth and reproduction processes of D. magna.