Hepatobiliary disposition of valproic acid and valproate glucuronide: Use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions
✍ Scribed by C L Booth; G M Pollack; K L Brouwer
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 271 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
with phenobarbital-associated impairment of canalicu-Previous work in this laboratory has suggested that lar egress of some organic anions. This work further supthe nonlinear disposition of valproic acid (VPA) in the ports the utility of pharmacokinetic modeling in: (1) derat may be due to nonlinear distribution of VPA into the termining the rate-limiting steps in hepatobiliary drug liver. The present study was undertaken to elucidate disposition and (2) identifying sites of drug interactions further the hepatobiliary disposition of VPA. VPA (0.1-2 within the hepatobiliary system that may not be evident mmol/L) was incubated with isolated rat hepatocytes in based on conventional mass-balance analysis. (HEPATOLvitro. Uptake of [ 3 H]-VPA was linear from 10 to 50 sec-OGY 1996;23:771-780.) onds, with minimal (õ7%) biotransformation. The initial velocity of VPA uptake varied in proportion with the extracellular concentration and was temperature independent, suggesting that VPA traverses the hepatocyte
The hepatic disposition of xenobiotics is influenced membrane predominantly by passive diffusion. In sepaby several factors, including uptake into the hepatorate studies, the hepatobiliary disposition of VPA (20 cyte, intracellular translocation, biotransformation, mg) was examined in the isolated perfused rat liver and egress into blood and/or bile. These processes may (IPL). A pharmacokinetic model was developed to deinvolve carrier-mediated mechanisms that are saturascribe the influence of phenobarbital on the hepatobilible and/or rate-limiting. The large number of structurary disposition of VPA and valproate glucuronide (V-G) ally unrelated compounds that are eliminated via the in the IPL; all processes governing VPA and V-G disposiliver suggests that multiple transport systems may be tion appeared to be linear. Acute administration of responsible for the hepatic translocation of substrates. 1 phenobarbital to the liver (1.12 mg) decreased the rate Alterations in hepatic transport systems can impair constant for canalicular egress of V-G (0.0489 { 0.0266 vs. 0.164 { 0.075 min 01 ). In vivo pretreatment with pheno-the biliary excretion of xenobiotics. 2 For example, phebarbital (75 mg/kg/d 1 5 d) before liver isolation denobarbital pretreatment impaired the biliary excretion creased the biliary excretion of both VPA (1.06E-04 of acetaminophen glucuronide and acetaminophen sul-{ 0.27E-04 vs. 2.76E-04 { 0.45E-04 min 01 ) and V-G (5.63Efate in vivo. [3][4][5] Biliary excretion of morphine and mor-03 { 1.98E-03 vs. 1.74E-02 { 0.5E-02 min 01 ), and increased phine glucuronide, 6 as well as valproic acid (VPA) and the apparent volume of distribution of VPA (84.6 { 2.2 valproate glucuronide (V-G), 7 were decreased after phevs. 72.3 { 2.1 mL). In vivo phenobarbital pretreatment nobarbital pretreatment in rats. changed V-G excretion from a formation to an elimina-VPA (2-propylpentanoic acid), an anticonvulsant eftion rate-limited process. These results are consistent fective in the treatment of various types of generalized and partial seizures, is an aliphatic carboxylic acid that exists predominantly in the ionized form at physiologi-Abbreviations: VPA, valproic acid; V-G, valproate glucuronide; IPL, isolated perfused liver; AIC, Akaike's Information Criterion. cal pH. VPA undergoes extensive hepatic metabolism From the Division of Pharmaceutics, School of Pharmacy, The University via b-(mitochondrial) and v-(microsomal) oxidation of North Carolina at Chapel Hill,