Distribution Of Valproic Acid Research Articles

Interaction Between Valproic Acid and Carbapenem Antibiotics

The serum concentration of valproic acid (VPA) in epilepsy patients decreased by the administration of carbapenem antibiotics, such as meropenem, panipenem or imipenem, to a sub-therapeutic level. This review summarized several case reports of this interaction between VPA (1–4 g dose) and carbapenem antibiotics to elucidate the possible mechanisms decreasing VPA concentration by carbapenem antibiotics. Studies to explain the decrease were carried out using rats by the following sites: absorption of VPA in the intestine, glucuronidation in the liver, disposition in blood and renal excretion. In the intestinal absorption site, there are two possible mechanisms: inhibition of the intestinal transporter for VPA absorption by carbapenem antibiotics, and the decrease of β-glucuronidase supplied from enteric bacteria, which were killed by antibiotics. This is consistent with a view that the decrease of VPA originated from VPA-Glu, relating to entero-hepatic circulation. The second key site is in the liver, because of no decreased in VPA level by carbapenem antibiotics in hepatectomized rats. There are three possible mechanisms in the liver to explain the decreased phenomenon: first, decrease of the UDPGA level by carbapenem antibiotics. UDPGA is a co-factor for UDP-glucuronosyltransferase (UGT)-mediated glucuronidation of VPA. Second, the direct activation of UGT by carbapenem antibiotics. This activation was observed after pre-incubation of human liver microsomes with carbapenem antibiotics. Third, the inhibition of β-glucuronidase in liver by carbapenem antibiotics and the decreased VPA amount liberated from VPA-Glu. The third site is the distribution of VPA in blood (erythrocytes and plasma). Plasma VPA distributed to erythrocytes by the inhibition of transporters (Mrp4), which efflux VPA from erythrocytes to plasma, by carbapenem antibiotics. The increase of renal excretion of VPA as VPA-Glu depends on the increase of VPA-Glu level by UGT. One or a combination of some factors in these mechanisms might relate to the carbapenem-mediated decrease of the plasma VPA level.

Valproate metabolites in the rat brain--regional distribution in various brain areas.

To investigate the regional distribution of valproic acid (VPA) and 10 of its metabolites in the rat brain, the animals were treated with 300 mg/kg/day VPA i.p. on a 3 times daily dose regimen for 5 days, and the concentrations of the compounds in serum and 15 brain regions were measured. 2-(n-propyl)-(Z)-2-pentenoic acid [(Z)-2-en], a VPA metabolite expected to possess neurotoxic potency in humans, was determined in brain tissue for the first time. The brain/serum concentration ratio of (Z)-2-en was found to be about 14-fold higher than the ratio for its (E)-isomer, thereby demonstrating the influence of the double-bond configuration in the unsaturated metabolites on their ability to penetrate into the central nervous system. The concentrations of VPA and its metabolites in the brain regions were compared to c(hom), the calculated concentration for an assumed homogeneous distribution. The parent drug and its metabolites exhibited individual distribution patterns with varying degrees of inhomogeneity. Elevated metabolite concentrations were found especially in the motorium and the medulla oblongata. Decreased concentrations of VPA and several metabolites were found in the visual cortex.

Analysis of tissue distribution of valproate in guinea-pigs: evidence for its capacity-limited tissue distribution.

The tissue distribution of valproic acid (VPA) was investigated over a wide range of steady-state plasma levels (Css) in guinea-pigs. The VPA concentrations in various tissues, except the kidney, were all lower than in plasma. Tissue-to-unbound plasma concentration ratios (Kpu) of VPA for adipose, heart, kidney, liver, lung, muscle, pancreas and skin all decreased significantly with increasing unbound plasma concentration (Cuss). The Kpu for brain (0.5-0.9), intestine, spleen and stomach failed to show significant change with Cuss. The disposition of VPA in tissues is adequately described by a model in which VPA was distributed in interstitial and intracellular fluid and bound to interstitial albumin, with limited tissue binding. Tissue binding was extensive only in the kidney. Most of the measured apparent Kpu values agreed well with simulated Kpu values. Steady-state tissue concentration of VPA can be predicted from Css and Cuss when reference data for interstitial albumin and tissue total water are available.

Low and variable presence of valproic acid in human brain

We studied the distribution of valproic acid (VPA) between brain (gray matter) and serum in 13 patients receiving chronic VPA therapy who underwent cortical resections for intractable seizures. Valproate concentration in cerebral cortex was remarkably low compared with either total or unbound valproate concentration in serum. The respective brain-to-serum partition ratios based on total and free drug in serum were 0.111 +/- 0.051 and 0.544 +/- 0.175. In comparison with other commonly used antiepileptic drugs, valproate has the distinction of exhibiting the lowest brain-to-blood partitioning. Moreover, the brain-to-serum concentration ratio varied over a four-fold range between patients. Some of this variability was related to variation in serum protein binding, as indicated by a modest correlation between the partition ratio and serum free fraction (r = +0.687). However, the brain-to-unbound concentration ratio still showed a three-fold variation. The variability in distribution of VPA between brain and blood is probably one of the underlying factors for the lack of a clearly definable therapeutic range of serum VPA concentration in epileptic patient populations.

Blood content in guinea-pig tissues: Correction for the study of drug tissue distribution

The blood content in different organs or tissues of guinea-pigs was determined by means of [ 125I]bovine serum albumin. The blood distribution expressed as percentage of total body blood for various organs or tissues ranged from 0.35 (adipose) to 17.5 (muscle) %. The blood content in tissue preparations expressed as the blood background correction factor, F (ml blood/g wet tissue) depended on the extent of bleeding during experiment; that factor can cause a considerable difference in the results of a tissue distribution study of a drug. Blood content was high in the lung (0.36 ml/g). heart, liver, kidney and spleen, but low in adipose and brain tissues (0.021 ml/g). The distribution of valproic acid in various tissues of guinea-pigs after intravenous injection was determined from the homogenates of isolated organs. The results showed that blood contamination can greatly alter the data of tissue distribution of a drug to as much as 25%. This study proposed a maximum (non-bled) and a minimum (extreme-bled) blood background correction factor for respective tissues of guinea-pigs, as well as equations for correcting the blood contamination in tissue during the drug distribution study. The results suggest that to obtain an exact analysis of drug concentrations in specific tissues, a correction for the blood of that specific tissue is necessary.