Biomedical subjects

G M Pollack

Publications and source records attributed to G M Pollack.

83 records · Page 5Linked to original sources

PubMedDate not supplied

Accumulation and washout kinetics of valproic acid and its active metabolites.

There is growing evidence that the metabolites of valproic acid (VPA) may be pharmacologically active and could contribute to both the therapeutic and toxic effects of the drug. The accumulation and washout kinetics of VPA and its oxidative metabolites were, therefore, examined in five healthy volunteers. Valproic acid (250-mg capsules) was administered bid for 15 days. Blood samples were obtained periodically during the 15 days of drug administration and for seven days following termination of treatment. Urine was also collected over the final dosing interval. Steady-state serum concentrations of VPA were achieved within three to four days of treatment. The accumulation of all metabolites in serum lagged behind that of the parent compound, with the mono-desaturated metabolites accumulating more slowly than the hydroxylated species. Furthermore, the apparent washout half-life of each metabolite was longer than the elimination half-life of VPA. In general, the unsaturated metabolites were eliminated more slowly than the hydroxylated metabolites. The serum and urinary metabolite profiles of VPA observed in the healthy volunteers were comparable with those reported for epileptic patients. The differences in the disposition kinetics of VPA and of its potentially active metabolites may explain the previously observed dissociation between the pharmacokinetics and pharmacodynamics of the drug in epileptic patients.

Adult↗

PubMedDate not supplied

Valproate metabolites and hepatotoxicity in an epileptic population.

Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4-en-VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4-en-VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4-en-VPA correlated with older age and absence of encephalopathy. 4-en-VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2-en-VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4-en-VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4-en-VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4-en-VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was detected only in patients receiving polytherapy, a potent risk factor for developing this rare complication.

Adolescent↗

PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. I. Spiro[4.6]undecane-2-carboxylic acid.

The pharmacokinetic and pharmacodynamic properties of the spiro carboxylic acid, spiro[4.6]undecane-2-carboxylic acid (SUCA, ADD 93024), were investigated in rats and compared with those of the standard anticonvulsant carboxylic acid, valproate (VPA). The clearance of SUCA was dose-dependent, although the observed nonlinearity did not appear to be due to classical saturable elimination. The change in clearance across doses was consistent with end-product inhibition or cosubstrate depletion. The volume of distribution of the spiro compound also evidenced nonlinearity, possibly due to concentration-dependent binding to serum proteins. In contrast, the dose-dependent clearance displayed by VPA was composed of both saturable and nonsaturable components. Furthermore, the disposition of VPA was characterized by a significant enterohepatic recirculation, whereas no such recirculatory process was apparent for SUCA. Both compounds afforded significant protection from pentylenetetrazol (PTZ)-induced seizures, and the time course of anticonvulsant effect did not correspond to that of drug concentrations in serum for either anticonvulsant. The apparent dissociation between the pharmacokinetics and pharmacodynamics of VPA may be a function of the mechanism of antiepileptic action and not due to the presence of active metabolites of the drug.

Animals↗

PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid.

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency. Both CCA and MCCA appeared to have an approximate twofold advantage relative to VPA in protective index (i.e., the ratio of concentrations that produce toxicity to concentrations that produce anticonvulsant effect), based on a rotorod assay of neurotoxicity. Examination of the time course of PTZ antagonism indicated that there was significant dissociation between pharmacokinetics and pharmacodynamics of VPA, with a marked delay in production of maximal anticonvulsant activity. In contrast, only a slight delay in production of maximal protection against PTZ-induced seizures was observed for MCCA, and no delay was evident for CCA. The data indicate that the dynamics of anticonvulsant action differ between these low-molecular-weight carboxylic acids despite their similar chemical structures.

Animals↗

PubMedDate not supplied

A pharmacokinetic model of inhaled methanol in humans and comparison to methanol disposition in mice and rats.

We estimated kinetic parameters associated with methanol disposition in humans from data reported in the literature. Michaelis-Menten elimination parameters (Vmax = 115 mg/L/hr; Km = 460 mg/L) were selected for input into a semi-physiologic pharmacokinetic model. We used reported literature values for blood or urine methanol concentrations in humans and nonhuman primates after methanol inhalation as input to an inhalation disposition model that evaluated the absorption of methanol, expressed as the fraction of inhaled methanol concentration that was absorbed (phi). Values of phi for nonexercising subjects typically varied between 0.64 and 0.75; 0.80 was observed to be a reasonable upper boundary for fractional absorption. Absorption efficiency in exercising subjects was lower than that in resting individuals. Incorporation of the kinetic parameters and phi into a pharmacokinetic model of human exposure to methanol, compared to a similar analysis in rodents, indicated that following an 8-hr exposure to 5000 ppm of methanol vapor, blood methanol concentrations in the mouse would be 13- to 18-fold higher than in humans exposed to the same methanol vapor concentration; blood methanol concentrations in the rat under similar conditions would be 5-fold higher than in humans. These results demonstrate the importance in the risk assessment for methanol of basing extrapolations from rodents to humans on actual blood concentrations rather than on methanol vapor exposure concentrations.

Animals↗

PubMedDate not supplied

Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites.

Acute toxicity in the setting of valproic acid (valproate sodium) overdose is in most cases benign and readily reversible. However, serious toxicity has been reported. We present a case of accidental acute valproic acid overdose in a 26-month-old female, in whom serious neurological, metabolic, haematological and respiratory sequelae occurred. The major toxicity observed was delayed cerebral oedema. We also present data not previously reported, which describes the pharmacokinetic disposition of valproic acid and several of its metabolites during the course of this acute overdose. A comparison of an enzyme immunoassay and gas liquid chromatographic methodologies for measuring valproic acid in this setting is also presented. It appears that the 2-EN-valproic acid metabolite plays a role in the neurological toxicity.

Brain Edema↗

PubMedDate not supplied

Pharmacokinetics and pharmacodynamics of valproate analogs in rats. III. Pharmacokinetics of valproic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid in the bile-exteriorized rat.

The pharmacokinetics of valproic acid (VPA) and its structural analogs cyclohexanecarboxylic acid (CCA) and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) were examined in bile-exteriorized rats. A 0.52 mmol/kg dose (equivalent to 75 mg/kg VPA) of test compound (N = 4 rats per compound) was administered as an intravenous bolus. VPA, CCA, and MCCA concentrations in serum, bile, and urine were determined by gas chromatography before and after incubation in sodium hydroxide to hydrolyze base-labile conjugates. Concentration-time profiles of these compounds in serum displayed apparent Michaelis-Menten kinetics. Serum concentrations of base-labile conjugates were similar to parent concentrations for VPA, were an order of magnitude lower than parent concentrations for CCA, and were undetectable for MCCA. Urinary recovery of base-labile (apparently glucuronide) conjugates in the bile-exteriorized rat was 28.8%, 12.0%, and 25.2% of the administered dose for VPA, CCA, and MCCA, respectively. In contrast, more than 50% of the dose for VPA and MCCA was recovered in bile as the base-labile conjugate, with less than 5% of the CCA dose recovered via this excretory route. Bile flow was stimulated significantly by VPA and MCCA, but not by CCA; changes in bile flow correlated with the biliary excretion rate of base-labile conjugates rather than with excretion of the parent compounds themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Chronic stress impairs oxidative metabolism and hepatic excretion of model xenobiotic substrates in the rat.

Traumatic injury to both hard and soft tissue has been associated with a decrease in the rate of hepatic drug metabolism. The mechanism(s) underlying this phenomenon have yet to be determined, but may involve substances released from damaged tissues or activation of the adrenocortical axis secondary to stress. To determine whether a generalized stress response is involved in the trauma-induced perturbations of xenobiotic metabolism, rats were exposed to atraumatic stress for a period of 21 days prior to determining the disposition of antipyrine (an in vivo marker for the hepatic mixed-function oxidase system) and indocyanine green (a tricarbocyanine dye often used as an in vivo marker of active hepatic uptake). Exposure to stress resulted in a significant decrease in the systemic clearance of antipyrine, suggesting a stress-induced inhibition of hepatic oxidation. In addition, the stressed animals evidenced a decreased rate of uptake of indocyanine green by the liver, an apparent decrease in the storage of the dye within the liver, and a decreased hepatic clearance of indocyanine green (presumably due to a decrease in the KM for biliary transport). These observations suggest that atraumatic stress affects several processes involved in the hepatobiliary disposition of xenobiotics.

Animals↗

PubMedDate not supplied

Determination of hepatic blood flow in the rat using sequential infusions of indocyanine green or galactose.

A method was developed for the estimation of hepatic blood flow in the rat using sequential infusions of one of two model substrates, indocyanine green or galactose. Either substrate was infused to steady state (achieved within 6 min of the start of indocyanine green infusion and within 40 min of the start of galactose infusion) through either the femoral or portal vein, and three steady state blood samples were obtained. Following a 30-min washout period, the same substrate was infused a second time through the alternate blood vessel. Using a pharmacokinetic approach, hepatic blood flow was estimated from the mean steady state concentrations during the two infusions and the infusion rate. The present method yielded hepatic blood flow estimates of 2.03 +/- 0.13 ml/min/g of liver (indocyanine green) and 2.28 +/- 0.49 ml/min/g of liver (galactose) in two groups of four adult male rats. A Monte-Carlo simulation experiment was conducted to assess the potential error introduced into the blood flow calculation by the moderate transhepatic extraction ratio of the two model substrates (0.386 +/- 0.049 for indocyanine green; 0.439 +/- 0.139 for galactose). The simulation experiment predicted calculational errors between 7.4% (indocyanine green) and 19.5% (galactose), based on the hepatic extraction ratio and the precision of the analytical method for the two compounds. The predicted errors were in good agreement with the variability in blood flow estimates observed experimentally (6.5% for indocyanine green; 21.4% for galactose). The steady state approach employed appears to be associated with superior reproducibility as compared to previously reported methods utilizing bolus dose administration of marker compounds and calculations based upon AUC estimates.

Animals↗

PubMedDate not supplied

Disposition and protein binding of valproic acid in the developing rat.

The disposition of valproic acid (VPA) in serum and brain tissue was examined in developing rats (5, 10, 20, and 60 days postpartum) following both single and multiple intraperitoneal doses of VPA. The binding of VPA to proteins in serum was determined ex vivo by ultrafiltration for each age group in pooled serum at various time points following VPA administration, as well as after in vitro addition of VPA (8-2400 micrograms/ml) to pooled rat serum from naive animals of each age. Concentration-time data for VPA in serum and brain tissue were fit simultaneously, assuming first-order absorption from the peritoneal injection site and first-order transfer of drug between serum and brain tissue. Kinetic analysis revealed that total clearance increased with postnatal age, whereas the volume of distribution and brain-to-serum partitioning of VPA decreased during development. Furthermore, enterohepatic recirculation, a well-described facet of VPA disposition in adult rats, was not evident from examination of the serum concentration-time profile in animals prior to the time of weaning. A progressive increase in the binding of VPA to proteins in serum was observed during postnatal development. The bound fraction determined ex vivo was less than that determined in vitro for all age groups, suggesting the possibility of competition for VPA binding sites by metabolite(s) formed in vivo.

Age Factors↗

PubMedDate not supplied

Site-dependent intestinal hydrolysis of valproate and morphine glucuronide in the developing rat.

A previous pharmacokinetic study in developing rats suggested that enterohepatic recirculation of valproic acid was absent prior to weaning. One explanation for this observation is that the rate, extent, and/or primary site of glucuronide hydrolysis in the gastrointestinal tract changes during postnatal development. To test this hypothesis, the hydrolysis of two model glucuronide conjugates, valproate glucuronide and morphine-3-beta,D-glucuronide, was examined in vitro in homogenates of small and large intestine obtained from rats at 5-60 days postpartum. Analysis of initial hydrolysis rates indicated that the principal hydrolytic site for both glucuronide conjugates shifted from the upper to lower intestine as the animals developed. The initial hydrolysis rate (nmol/min/g) for valproate glucuronide decreased from 38.1 +/- 10.2 to 8.25 +/- 2.42 in the small intestine, and increased from 14.2 +/- 2.3 to 105 +/- 22 in the large intestine, as rats developed from 5 to 60 days postpartum, respectively. Likewise, the intestinal hydrolysis rate for morphine-3-beta,D-glucuronide decreased from 3.70 +/- 0.46 to 0.646 +/- 0.165 in the small intestine, and increased from 3.50 +/- 0.48 to 115 +/- 30 in the large intestine, as rats developed from 5 to 60 days postpartum, respectively. If hydrolysis occurs immediately after excretion of conjugate into the intestine in neonatal rats, minimal temporal delay between excretion of conjugate and reabsorption of liberated parent may occur, therefore concealing the secondary increase in serum drug concentrations associated with enterohepatic recirculation. In contrast, the time required for conjugates to reach the primary hydrolytic site in adult animals is sufficient for appearance of secondary peaks in the serum drug concentration-time profile.

Age Factors↗