Biomedical Research

The aim of this study is to determine whether pramipexole hydrochloride hydrate (PHH) and atropine sulfate affect valproic acid (VPA) pharmacokinetics and to evaluate how plasma VPA concentrations are altered by different PHH administration routes. The following studies were conducted on rats: 1) changes in plasma VPA concentration after simultaneous oral administration (PO) of PHH and VPA-Na; 2) effects of intraperitoneal administration (IP) of PHH on plasma VPA concentration after VPA-Na PO; 3) effects of PHH PO on plasma VPA concentration after intravenous administration (IV) of VPA-Na; and 4) changes in plasma VPA concentration after simultaneous PO of atropine sulfate and VPA-Na. Atropine sulfate PO significantly decreased the area under the concentration-time curve up to 3 h (AUC0-3, the total amount of drug plasma concentration) of VPA, suggesting that atropine sulfate decreases VPA-Na absorption probably due to reduced gastrointestinal motility by its anticholinergic action. Similarly, by PHH PO or IP, VPA AUC0-3 was significantly decreased. However, in cases of VPA-Na IV, all VPA parameters were unchanged by PHH PO. These results indicate that the PHH inhibitory effect may be caused in the absorption phase of VPA by pharmacological action of PHH, and thus PHH decreases VPA-Na bioavailability. Sodium valproate (VPA-Na, monosodium 2-propylpentanoate) is a straight-chain alkyl monocarboxylic acid with the chemical formula C8H16O2. VPA-Na possesses a broad antiepileptic spectrum, and is used as a first-line treatment for patients with generalized and partial seizures (1, 11). It is strongly suggested that the pharmacological effects of VPA may increase the concentration of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter to brain neurons, or enhance the action of GABA at postsynaptic receptor sites (7). An unexpected change in valproic acid (VPA) concentration after VPA-Na administration might be caused by some co-administered drugs (9, 16). In addition, we reported that salicylate (15) and rizatriptan benzoate (8) affected plasma VPA concentration in rats. Therefore, many clinical situations may need reliable therapeutic drug monitoring of VPA for the appropriate dose because of unpredictable drug-interactions. Pramipexole hydrochloride hydrate (PHH, S2-Amino-4,5,6,7-tetrahydro-6-propylaminobenzothiazole dihydrochloride hydrate), a direct-acting dopamine receptor agonist, is effective in treatment of Parkinson’s disease, and selectively binds to dopamine D2 and D3 receptors with high affinity (13, 17, 22). VPA-Na is often prescribed in combination with PHH. It is known that dopamine agonists can depress gastrointestinal motility. Thus, in patients given PHH, it is considered that gastrointestinal motility declines due to the D2 receptor agonistic activity of PHH, subsequently affecting VPA pharmacokinetics. However, until now, there is no report addressing VPA-PHH interactions. Therefore, we investigated whether PHH and atropine sulfate, a Address correspondence to: Nobuo Hokama, Ph.D. Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan Tel: +81-98 895 1348, Fax: +81-98 895 1487 E-mail: hokama-ryk@umin.ac. jp H. Kameya et al. 102 tion after intravenous administration (IV) of VPANa. VPA-Na (100 mg/2 mL/kg dissolved in saline) was injected into the jugular vein of 10 rats (bw = 274–312 g) under ether anesthesia. Just after VPANa injection, PHH (4.5 mg/5 mL/kg dissolved in purified water) was given orally in 5 rats. As a control, purified water (5 mL/kg) was given to VPA-Natreated 5 rats. 4) Changes in plasma VPA concentration after simultaneous PO of atropine sulfate and VPA-Na. VPA-Na (100 mg/kg) was administered orally to 10 rats (bw = 280–320 g). Atropine sulfate (1 mg/5 mL/ kg dissolved in purified water) was administered orally just after VPA-Na PO in 5 rats. As a control, purified water (5 mL/kg) was similarly given to VPA-Na-treated 5 rats. Data analysis. VPA plasma concentrations were determined by a fluorescence polarization immunoassay (FPIA) using the TDXFLX analyzer (Abbott Laboratories, Abbott Park, USA). Pharmacokinetic parameters were obtained from VPA concentrations. Maximum plasma concentration (Cmax) of VPA and time to reach Cmax (Tmax) were estimated from actual measurements. Elimination rate constant (Kel) was determined by a linear least-square regression analysis using the natural logarithm of the VPA plasma concentrations measured at 1, 2 and 3 h after PO and IV. VPA plasma elimination half-life was calculated from 0.693/Kel, and the area under the concentration-time curve up to 3 h (AUC0-3) values was calculated using the linear trapezoidal rule. Results were expressed as mean ± standard errors (SEM). The Mann-Whitney U test was used to examine drug interactions. Assessment of statistical significance was based on P < 0.05. Stat View program (version 5.0; SAS Institute, Cary, NC) was used for statistical analyses.