Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid

Valproic acid (VPA) is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC) administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125mg were administered three times daily for 7days and then a single dose of VPA was administered. Blood samples were collected up to 48hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUC_last, 851.0 h⋅mg/L vs 889.6 h⋅mg/L; C_max, 52.1mg/L vs 53.0mg/L). There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI]) of AUC_last and C_max (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively). Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary.