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G M Pollack

Publications and source records attributed to G M Pollack.

At least 55 records · Page 3Linked to original sources
PubMed1996

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.

Previous work in this laboratory has suggested that the nonlinear disposition of valproic acid (VPA) in the rat may be due to nonlinear distribution of VPA into the liver. The present study was undertaken to elucidate further the hepatobiliary disposition of VPA. VPA (0.1-2 mmol/L) was incubated with isolated rat hepatocytes in vitro. Uptake of [(3)H]-VPA was linear from 10 to 50 seconds, with minimal (<7 percent) biotransformation. The initial velocity of VPA uptake varied in proportion with the extracellular concentration and was temperature independent, suggesting that VPA traverses the hepatocyte membrane predominantly by passive diffusion. In separate studies, the hepatobiliary disposition of VPA (20mg) was examined in the isolated perfused rat liver (IPL). A pharmacokinetic model was developed to describe the influence of phenobarbital on the hepatobiliary disposition of VPA and valproate glucuronide (V-G) in the IPL; all processes governing VPA and V-G disposition appeared to be linear. Acute administration of phenobarbital to the liver (1.12 mg) decreased the rate constant for canalicular egress of V-G (0.0489 +/- 0.0266 vs. 0.164 +/- 0.075 min(-1)). In vivo pretreatment with phenobarbital (75 mg/kg/d x 5 d) before liver isolation decreased the biliary excretion of both VPA (1.06E-04 +/- 0.27E-04 vs. 2.76E-04 +/- 0.45E-04 min(-1)) and V-G (5.63E- 03 +/- 1.98E-03 vs. 1.74E-02 +/- 0.5E-02 min(-1)), and increased the apparent volume of distribution of VPA (84.6 +/- 2.2 vs. 72.3 +/- 2.1 mL). In vivo phenobarbital pretreatment a changed V-G excretion from a formation to an elimination rate-limited process. These results are consistent with phenobarbital-associated impairment of canalicular egress of some organic anions. This work further supports the utility of pharmacokinetic modeling in: (1) determining the rate-limiting steps in hepatobiliary drug disposition and (2) identifying sites of drug interactions within the hepatobiliary system that may not be evident based on conventional mass-balance analysis.

Animals↗
PubMed1996

Use of intrauterine microdialysis to investigate methanol-induced alterations in uteroplacental blood flow.

Methanol is teratogenic in rodents; it has been postulated that this teratogenicity may be mediated in part by conceptal hypoxia. To construct a model to predict conceptal risk following maternal methanol exposure, conceptal disposition of methanol must be determined and any effects of such exposure on blood flow must be quantitated. In the present study, these toxicokinetic and toxico-dynamic parameters were evaluated by in vivo intrauterine microdialysis. Microdialysis probes were inserted into the uteri of Gestational Day (gd) 20 rats; methanol was administered as either an iv bolus (100 or 500 mg/kg) or infusion (100 or 1000 mg/kg/hr). In separate experiments, methanol (100 or 500 mg/kg) and 3H2O (20 microCi/kg) were administered iv to gd 20 and 14 rats and gd 18 mice. In both experiments, maternal blood and uterine microdialysate were collected and analyzed for methanol or 3H2O content. The methanol concentration-time data were consistent with saturable maternal elimination and apparent first-order transfer between maternal and conceptal compartments; at distribution equilibrium, conceptal methanol concentrations exceeded those in the dam by approximately 25%. The initial rate of conceptal permeation of methanol was proportional to the reciprocal of maternal blood methanol concentration (r2 = 0.910). Methanol also reduced significantly the rate of 3H2O uptake into the conceptus in a concentration-dependent fashion in gd 14 and 20 rats and gd 18 mice. These data indicate that methanol may decrease uteroplacental blood flow, decreasing methanol presentation to the conceptus and possibly producing conceptal hypoxia.

Administration, Intravaginal↗
PubMed1996

Anticonvulsant pharmacodynamics and disposition of triazolam in rats.

Triazolam (TZ) is a triazolobenzodiazepine used in the treatment of insomnia that possesses significant anticonvulsant properties. Despite the widespread use of this drug, detailed pharmacokinetic-pharmacodynamic information is lacking, especially with respect to inhibition of seizure activity. TZ disposition has been described previously by methods with limited specificity, and the concentration-anticonvulsant effect relationship has not been characterized. The current studies were undertaken to examine TZ disposition with a specific HPLC method, and to evaluate the relationship between anticonvulsant effect and concentration in Sprague-Dawley rats. TZ pharmacokinetics were characterized after bolus or infusion administration; in a separate experiment, TZ pharmacodynamics were assessed with pentylenetetrazol-induced seizures. The systemic disposition of TZ could be described with a two-compartment model; systemic clearance ranged from 2.45 to 5.30 L/h/ kg, steady-state volume of distribution ranged from 2.10 to 4.02 L/kg, and mean residence time ranged from 47 to 65 min. The concentration-effect relationship was well described by a simple Emax model: Emax, expressed as the ratio of post-TZ to pre-TZ threshold convulsant doses of pentylenetetrazol, was 9.9 +/- 0.7, and the EC50 values were 10.0 +/- 4.6 ng/mL and 34.8 +/- 9.0 ng/g in serum and whole brain tissue, respectively. Under single-dose conditions, TZ is a very potent anticonvulsant in the rat pentylenetetrazol seizure model.

Animals↗
PubMed1996

Age-related changes in valproic acid binding to rat serum proteins in vitro.

The effect of age on the in vitro binding of valproic acid (VPA) to serum proteins was investigated in rats ranging in age from 14 days (preweaning) to 24 months (senescent). The influence of free fatty acid (FFA) and total protein (TP) concentrations on age-related changes in binding was examined. The protein binding of VPA was altered during development and aging. The VPA fraction unbound (fu) at low VPA concentrations was significantly higher in older age groups (12 and 24 months old; fu = 0.26-0.30) than in younger animals (14, 20, and 40 days old; fu = 0.16-0.18). Binding was best described by a model incorporating a saturable and a nonsaturable binding site. Binding affinity at the saturable binding site was lowest at the extremes of age. Changes in binding at either the saturable or the nonsaturable site were not predicted by changes in TP or FFA with age. Changes in nonsaturable binding were marginally associated with age (p = 0.0952). A 3-fold increase in FFA concentrations was necessary to produce a 1.5-fold increase in VPA fu. There was less than a 2-fold difference in FFA concentrations between the age groups (range 0.219-0.379 mmol/L). Thus, the difference in FFA concentrations between the age groups may not have been large enough to cause measurable differences in displacement of VPA from binding sites. Changes in protein binding may contribute to age-related changes in disposition of VPA observed in the rat. Changes in the serum concentrations of specific FFA or proteins may play a role in the altered VPA binding with age, but changes in total FFA or protein concentrations do not account for the age-related differences observed. Further investigation is required to identify the mechanism(s) responsible for age-related changes in binding of VPA to serum proteins measured in vitro.

Age Factors↗
PubMed1996

Physiologic pharmacokinetic modeling of gastrointestinal blood flow as a rate-limiting step in the oral absorption of digoxin: implications for patients with congestive heart failure receiving epoprostenol.

A previously validated physiologically based pharmacokinetic model was used to examine whether epoprostenol-induced increases in gastrointestinal blood flow (Qg) could alter digoxin systemic bioavailability to a clinically significant extent in severe congestive heart failure (CHF) patients. A series of simulations was conducted in which the influences of apparent gut tissue-to-plasma partition coefficient (Kg) and Qg on digoxin bioavailability were evaluated. Since epoprostenol also increases blood flow to the liver and kidneys, the effect of concurrent increases in regional blood flow to these organs on digoxin bioavailability also was evaluated. A range of Qg was studied from 25 L/h (assumed mesenteric arterial flow in CHF) to 65 L/h (portal venous flow in normal adults), and the area under the simulated digoxin concentration-time curve was used to calculate absolute digoxin bioavailability in each case. Simulations were conducted at a range of Kg from 1 to 50 (physiologically relevant range 5-25). At low values of Kg, the influence of changes in Qg on digoxin bioavailability was minimal. However, as apparent distribution into gut tissue increased (consistent with visceral congestion), the effect of changes in Qg was more substantial. In the physiologically relevant range of Kg, 40-160% increases in Qg were associated with approximately 6-40% increases in digoxin bioavailability. Therefore, the decrease in digoxin oral clearance previously observed in CHF patients receiving epoprostenol may be ascribed to increases in digoxin bioavailability, secondary to epoprostenol-induced increases in Qg.

Adult↗
PubMed1996

Methanol inhalation: site and other factors influencing absorption, and an inhalation toxicokinetic model for the rat.

PURPOSE: This investigation was conducted to identify the site and characteristics of methanol absorption and to develop an inhalation model relating methanol absorption, blood concentration, and elimination. METHODS: Rats were exposed to methanol in chambers that allowed measurement of methanol uptake, ventilation, and blood concentrations; anesthetized rats with a tracheal cannula were examined to determine tracheal concentrations. In separate experiments, methanol exposed rats received an iv methanol bolus to examine the effect of blood methanol on ventilation and absorption; ventilation also was manipulated by CO(2) or pentobarbital to assess the effect of ventilation rate on methanol absorption. These data were combined to construct a semi-physiologic model of methanol uptake. RESULTS: Only 1-3 percent of inhaled methanol reached the trachea, primarily from systemic methanol partitioning into the trachea; blood methanol did not alter methanol absorption. Manipulation of ventilation and application of the pharmacokinetic model indicated that ventilation was less significant than environmental methanol concentration in determining the fraction of inhaled methanol absorbed, although both parameters were important determinants of the total mass absorbed. CONCLUSIONS: These data indicate that methanol uptake is a complex process that depends upon several parameters. Despite these complexities, a relatively simple semi-physiologic model was capable of describing methanol uptake over a wide range of exposure concentrations in the rat.

Administration, Inhalation↗
PubMed1996

Maternal-fetal pharmacokinetics of methanol.

We undertook the present project to elucidate the physiologic factors that govern methanol delivery to the developing conceptus after maternal methanol exposure, and to develop a physiologically based toxicokinetic model to describe methanol disposition in pregnancy. A multi-experimental approach addressed the goals of this project. Initial experiments characterized the systemic disposition of methanol after intravenous or oral administration to nonpregnant female rats. Methanol absorption from the gastrointestinal tract was rapid (peak concentrations appeared within 1 to 2 hours after administration) and essentially complete (systemic bioavailabilities ranged from approximately 0.6 to 1.0). As anticipated for short-chain aliphatic alcohols, methanol elimination from the systemic circulation was nonlinear due to saturation of the metabolic route or routes responsible for converting methanol to formaldehyde and, ultimately, formic acid. However, a significant parallel linear route of methanol elimination was observed, which accounted for an increasingly significant fraction of total elimination as methanol doses (or systemic concentrations) increased. The disposition of methanol after oral or intravenous administration was similar in pregnant and nonpregnant female rats, regardless of the gestational stage (day 7, 14, or 20 after conception) at which the toxicokinetics of methanol were examined. This observation indicated that data from nonpregnant subjects could be used in the development of the maternal portion of a comprehensive physiologic model for methanol disposition. Parallel experiments in female mice indicated that methanol elimination was approximately twice as rapid in mice as in rats due to a significantly higher maximal velocity for methanol metabolism in the smaller rodent species. As was the case in the rat, relatively small changes in methanol elimination were observed during the course of gestation in pregnant mice. In both species, the rate of methanol metabolism by fetal liver in vitro was less than 10% that of the metabolic rate in adult liver. The kinetics of methanol delivery into the fetal environment were examined by determining amniotic fluid concentrations of methanol after intravenous administration to pregnant rats. The net rate of methanol translocation from maternal blood to amniotic fluid decreased as methanol concentration increased. Although the mechanism of this anomalous result is unknown, it possibly is due to a methanol-induced decrease in blood flow to the fetus.

Administration, Oral↗
PubMed1996

Comparative toxicokinetics of methanol in pregnant and nonpregnant rodents.

Methanol toxicokinetics were examined in pregnant Sprague-Dawley rats and CD-1 mice to explore the possibility of gestational-associated alterations in metabolism and disposition. In vitro biotransformation of methanol in rat and mouse fetal livers also was examined to assess the capability of the near-term rodent fetus to metabolize methanol. In the in vivo studies, rats received a single dose (100 or 2,500 mg/kg) of methanol either orally (by gavage) or intravenously; mice received a single oral or intravenous 2500-mg/kg dose. The maximal rate of methanol elimination (Vmax) in vivo decreased at term in both rodent species; Vmax in near-term rats and mice was only 65-80% of that in nonpregnant animals. Gestation also affected intercompartmental transfer rate constants, although there was no obvious relationship between these changes and gestational stage. In vitro metabolism studies supported the in vivo data; adult near-term rodent livers metabolized methanol with a Vmax of approximately 85% that in livers from nonpregnant rodents (p < 0.05). Fetal rodent liver was capable of metabolizing methanol in vitro, but only at a rate < 5% of respective adult livers. Data generated in these experiments demonstrate that alterations in methanol disposition associated with gestational stage must be accounted for in the development of a toxicokinetic model for methanol in pregnant mammals.

Administration, Oral↗
PubMed1995

Comparative toxicokinetics of methanol in the female mouse and rat.

The toxicokinetics of methanol in female CD-1 mice and Sprague-Dawley rats were examined to explore the possibility of species differences in the disposition of the compound. Mice received a single dose of 2.5 g/kg methanol either po (by gavage) or i.v. (as a 1-min infusion). Rats received a single oral dose of 2.5 g/kg methanol. As expected, the disposition of methanol was nonlinear in both species. Data obtained after i.v. administration of methanol to mice were well described by a one-compartment model with Michaelis-Menten elimination. Blood methanol concentration--time data after oral administration could be described by a one-compartment (mice) or two-compartment (rats) model with Michaelis-Menten elimination from the central compartment and biphasic absorption from the gastrointestinal tract. Kinetic parameters (Vmax for elimination, apparent volume of the central compartment [Vc], first-order rate constants for intercompartmental transfer [k12 and k21], and first-order absorption rate constants for fast [kAF] and slow [kAS] absorption processes) were compared between species. When normalized for body weight, mice evidenced a higher maximal elimination rate than rats (Vmax = 117 +/- 3 mg/hr/kg vs 60.7 +/- 1.4 mg/hr/kg for rats). The contribution of the fast absorption process to overall methanol absorption also was larger in the mouse than in the rat.

Administration, Oral↗
PubMed1995

Comparative toxicokinetics of inhaled methanol in the female CD-1 mouse and Sprague-Dawley rat.

Female CD-1 mice were exposed for 8 hr, both individually and in groups of eight to nine, to 2500, 5000, and 10,000 ppm methanol vapor in a flowthrough exposure chamber. The ventilation of individually exposed mice and the absorption of methanol from the chamber airstream were measured. The extraction of methanol from the airstream and the blood methanol concentration at various time points during and following exposure were determined for the group-exposed mice. The similarity of systemic kinetic parameters (volume of distribution; Michaelis-Menten elimination parameters, Vmax and KM) between inhalation exposure and iv and po routes of administration was verified. Total 8-hr ventilation decreased slightly with increasing exposure concentration. The fraction of inhaled methanol absorbed (0.85 +/- 0.14) did not vary statistically with exposure concentration. Measured ventilation, fractional absorption, and systemic kinetic parameters were combined in a semiphysiologic pharmacokinetic model that yielded accurate predictions of blood methanol concentrations during and after an 8-hr exposure. Model predictions for the mouse were compared to a previously developed inhalation toxicokinetic model for the rat. The comparison demonstrated that at similar methanol vapor concentrations, mice evidenced a two- to threefold higher blood methanol concentration than rats, despite the fact that the apparent Vmax for methanol elimination in the mouse is twofold larger than that in the rat. These data may have significant implications in understanding species differences in methanol-induced teratogenic effects.

Absorption↗
PubMed1995

A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats.

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50 degrees C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.0 mg/kg per hr) or saline. Morphine-induced antinociception, expressed as the percentage of maximum possible response (% MPR), peaked after 120 min of infusion and decreased thereafter despite sustained systemic morphine concentrations. Both the rate and extent of tolerance development increased with increasing concentrations; an overall residual effect of approximately 24% MPR was observed at the end of the infusion regardless of the steady-state morphine concentration. The kinetics of tolerance offset were examined in a separate experiment by assessing tail-flick latency 15 min after morphine iv bolus (2 mg/kg) in tolerant and control rats. Recovery of response neared completion 18.5 days after a 12-hr exposure to morphine (2.0 mg/kg per hr). A PK-PD model was constructed to account for the delay in onset of antinociceptive effect and tolerance development relative to the blood concentration-time profile. According to this model, both the extent and the rate of tolerance development were modulated by the kinetics of the drug in the central compartment. Accumulation of a hypothetical "inhibitor" acting either as a reverse agonist, a competitive or noncompetitive antagonist, or a partial agonist could potentially account for the loss of pharmacologic effect in the presence of an agonist. The rate of tolerance development predicted from the PK-PD model varied widely (28-fold) depending on the type of pharmacologic interaction selected to account for the loss of effect. Using the rate of tolerance offset to discriminate between the different models (t1/2 offset 5.4 days), onset and offset of tolerance was described accurately by postulating that the inhibitor behaves as a partial agonist with low intrinsic activity (5.5% MPR) and high binding affinity for the receptor (IC50 15.0 ng/ml).

Analgesia↗
PubMed1995

Pharmacokinetics and anticonvulsant effect of a new hypnotic, CL 284,846, in rats.

PURPOSE: CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats. METHODS: CL846 pharmacokinetics were examined after either an iv bolus dose (2.5 mg/kg) or a 6-hr infusion (0.4 mg/kg/hr). CL846 pharmacodynamics were evaluated with a pentylenetetrazol (PTZ) infusion 5 min after a CL846 in bolus dose (0 to 10 mg/kg). CL846 and the derived metabolite CL 284,859 (CL859) concentrations in serum and brain tissue were determined by HPLC with fluorescence detection. RESULTS: Both the steady-state volume of distribution (1636 +/- 162 and 1804 +/- 293 ml/kg, after bolus and infusion administration, respectively) and systemic clearance (19.1 +/- 7.1 and 22.2 +/- 4.3 ml/min/kg for bolus and infusion administration, respectively) were high. No differences in pharmacokinetic parameters were noted between the two modes of administration. The relationship between anticonvulsant effect and brain/serum concentrations was well described by an Emax model. CL846 was as effective as triazolam in antagonizing PTZ-induced seizures. CONCLUSIONS: Under the conditions of the present study, CL846 pharmacokinetics were linear and stationary. Further evaluation of the anticonvulsant properties of CL846 is warranted, including the potential development of tolerance, which is well known for benzodiazepines.

Acetamides↗
PubMed1995

Age-dependent intestinal absorption of valproic acid in the rat.

The absorption of valproic acid (VPA) across isolated perfused segments of jejunum, ileum and colon was examined in situ in 14-day- to 24-month-old Fischer-344 rats. Within each age group, the intrinsic absorptive clearance (Cla) of VPA at a perfusate concentration of 1 mg/ml was highest in the jejunum, lowest in the colon, and intermediate in the ileum. When intestinal Cla was normalized for the dry weight of the segment, within-group variability decreased. In all segments, VPA Cla normalized by dry weight decreased during development (< or = 20 to 90 days) and remained relatively constant during aging (90 days to 24 months). The mechanism of valproate absorption (active vs. passive) was examined across age in everted intestinal sacs prepared from each of the three segments. Data were consistent with active transport of VPA in the jejunum and ileum of rats of all ages, and in the colon of pre-weanling animals. Colonic absorption of VPA appeared to occur by passive diffusion in adult rats. In contrast, colonic absorption of d-glucose occurred, only by passive diffusion in all age groups. These data indicate that, during development, significant alterations in the rate of VPA absorption occur throughout the rat intestine. Furthermore, while active transport of VPA by the small intestine was present throughout the age range investigated, active transport by the colon became negligible by the time of weaning.

Aging↗
PubMed1995

Age-dependent intestinal hydrolysis of valproate glucuronide in rat.

1. Age-dependent differences in the intestinal hydrolysis of the glucuronide conjugate of valproic acid were evaluated in the Fisher-344 rat at 14 and 40 days, and 24 months of age. 2. Hydrolysis occurred more quickly when incubations were conducted under anaerobic as compared with aerobic conditions. 3. The rate of hydrolysis of valproate glucuronide was most rapid in the contents of the large intestine (caecum and colon); no difference in rate was noted between age groups during incubations with large intestinal contents. 4. Hydrolysis in the tissues of the large and small intestines, and the contents of the small intestine, was more rapid in the 14-day-old rat than in the older age groups. Differences in the rates and sites of hydrolysis in the 14-day-old animal may be due to regional differences in the number and types of microorganisms or mammalian beta-glucuronidase present in the gastrointestinal tract. 5. Differences in intestinal hydrolysis of valproate glucuronide may account in part for age-related changes in enterohepatic recirculation of valproate in young animals; other mechanisms apparently are responsible for altered valproate disposition in senescent animals.

Aging↗
PubMed1995

Biliary excretion and enterohepatic recirculation of morphine-3-glucuronide in rats.

Morphine elimination is characterized by a prolonged terminal elimination phase, at least in part because of enterohepatic recirculation (EHR) of morphine as its major metabolite, morphine-3-glucuronide (M3G). This experiment was conducted to characterize M3G disposition after direct administration of the metabolite to intact or bile duct-cannulated (BC) rats, and to develop a pharmacokinetic model of EHR for M3G. Male Sprague-Dawley intact and BC rats (N = 4/group) received a 5 mg/kg iv bolus of M3G, with serum and bile sampled at timed intervals after the dose; urine was collected in toto at the end of the experiment. M3G elimination from serum was rapid in BC rats; in contrast, M3G residence was prolonged in intact animals. M3G biliary excretion rate vs. time profiles paralleled the M3G serum concentration-time profiles in BC rats, with up to 20% of the dose recovered as M3G in bile. The remainder of the dose (80%) was recovered in urine as unchanged M3G. No morphine could be detected in urine after M3G administration. To confirm that biliary elimination of M3G occurred following uptake by the liver, M3G was administered to isolated perfused rat livers (N = 4). Up to 20% of the M3G dose was recovered in bile after 90 min, suggesting that systemic M3G can gain access to the liver and contribute to EHR. Both mean residence time and steady-state volume of distribution were significantly greater in intact rats, presumably because of EHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Protein binding and hepatobiliary distribution of valproic acid and valproate glucuronide in rats.

The protein binding and hepatobiliary distribution of valproic acid (VPA) and its glucuronide conjugate (V-G) were examined in rats with a combination of in vitro and ex vivo protocols. VPA was moderately bound to proteins in both serum and hepatic cytosol, and the degree of binding was lower ex vivo than in vitro. V-G, which was more highly bound than VPA ex vivo in serum, may have displaced the parent drug from its binding sites when VPA was administered in vivo. Examination of ex vivo hepatic subcellular distribution revealed that VPA localization tended to be high in cytosol and low in the microsomal fraction; V-G appeared to be distributed evenly throughout the cell although V-G concentrations within the liver were very low. The steady-state elimination rate of VPA did not increase proportionately with increasing steady-state concentrations of unbound VPA in serum, consistent with saturable systemic elimination of the drug. In contrast, steady-state VPA elimination was related linearly to unbound cytosolic VPA concentrations. Moreover, a nonlinear relationship between the unbound concentrations of VPA in hepatic cytosol and serum was observed, consistent with saturable distribution of the unbound drug between the two compartments in vivo. These observations suggest that the nonlinear elimination of VPA in rats may be due to concentration-dependent penetration of the drug into the liver as opposed to saturable biotransformation.

Animals↗
PubMed1993

Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid.

The pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA), were examined in female Sprague-Dawley rats. All four carboxylic acids evidenced dose-dependent disposition. A dose-related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose-dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose- and compound-dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base-labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base-labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis-Menten kinetics, although the calculated Km was dose-dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.

Animals↗