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G M Pollack

Publications and source records attributed to G M Pollack.

At least 73 records · Page 4Linked to original sources
PubMed1993

Toxicokinetics of intravenous methanol in the female rat.

The toxicokinetics of intravenously administered methanol were examined in female Sprague-Dawley rats. Animals received a single administration of 100, 500, or 2500 mg methanol/kg; the two lower doses were administered as a bolus, while the high dose was administered over 1.5 min. A small (approximately 3%) but statistically insignificant (p > 0.1) degree of transpulmonary methanol extraction, expressed as the fractional arterial-venous difference in concentration, was observed after administration of 250 mg methanol/kg. The elimination of methanol from the systemic circulation was markedly nonlinear, suggestive of a significant capacity-limited route of elimination. A single set of kinetic parameters (apparent distributional volume of the central compartment [Vc], intercompartmental transfer rate constants [k12 and k21], and Vmax and Km for elimination) described the blood methanol concentration-time data from rats receiving the 100 and 500 mg/kg doses. Blood methanol concentrations declined much more rapidly in animals receiving the 2500 mg/kg dose than would be predicted from the kinetic parameters derived from the other two experimental groups. The data from the 2500 mg/kg group could be described adequately by a kinetic model incorporating parallel first-order and saturable elimination processes. A portion of this apparent linear elimination pathway was due to renal excretion of the unchanged alcohol. The presence of both linear and nonlinear elimination pathways for methanol may have implications regarding high-dose to low-dose toxicologic extrapolations.

Animals↗
PubMed1993

Assessment of valproic acid serum-cerebrospinal fluid transport by microdialysis.

The systemic disposition and serum-cerebrospinal fluid (CSF) translocation of valproic acid (VPA) were examined in rats after administration of VPA as a bolus, as a continuous infusion, or with probenecid. VPA in CSF was monitored continuously by in vivo microdialysis. Both prolonged VPA infusion and probenecid pretreatment increased the Km for saturable VPA elimination and decreased intrinsic hepatic clearance, perhaps due to competition of probenecid or accumulated VPA metabolites for glucuronidation or depletion of hepatic UDP-glucuronic acid. The CSF/serum VPA ratio increased rapidly initially, then decreased with time throughout the remainder of the experiment in all three groups. This time- and/or concentration-dependent behavior suggested that the rate of CSF penetration increased disproportionately with increasing serum VPA and could be described by a kinetic model incorporating a concentration-dependent first-order rate constant for VPA influx into CSF. Under all experimental conditions, the VPA efflux from CSF appeared to be saturable; an increase in the Michaelis constant for efflux was observed following probenecid pretreatment and during VPA infusion, suggesting competitive inhibition of transport by probenecid and derived metabolites of VPA, respectively. The mechanisms responsible for asymmetric VPA transport between serum and CSF, in particular the apparent concentration-dependent change in the rate constant governing CSF penetration, remain to be elucidated.

Animals↗
PubMed1992

Use of a pharmacokinetic model incorporating discontinuous gastrointestinal absorption to examine the occurrence of double peaks in oral concentration-time profiles.

Double peaks in the plasma concentration-time profile following oral administration have been reported for several compounds. A pharmacokinetic model incorporating discontinuous absorption was developed to simulate concentration-time profiles with double peaks. The gastrointestinal (GI) tract was divided into N compartments, with absorption occurring only from the second and Nth compartments. A two-compartment model was used to describe systemic drug disposition. The effect of gastric emptying and GI transit rate constants (Kl and K1, respectively), number of hypothetical gut compartments, and absorption rate constant at each site (Ka1, Ka2) on the time of occurrence of each peak (Tp1, Tp2), the theoretical fraction of the dose absorbed at each site (phi 1, phi 2), and the contribution of the second site to systemic drug exposure (expressed as phi 2rel) were examined. Simulated concentration-time profiles demonstrated that Tp2 was determined by Kt and N, while Tp1 was determined by K1 and Kt. Changes in Ka1 and Ka2 had no effect on Tp1 or Tp2. phi 1, phi 2, and phi 2rel were determined by Ka1, Ka2, and Kt, and simulations indicated that a secondary peak in the concentration-time profile will be evident only when phi 2rel is substantial. In addition, concentration-time data for ranitidine and cimetidine, which displayed double peaks, were fit with the model. The present model described both data sets well, and realistic pharmacokinetic and physiologic parameters (absorption rate constants, systemic bioavailabilities, GI residence times) were obtained.

Administration, Oral↗
PubMed1991

Determination of methanol in whole blood by capillary gas chromatography with direct on-column injection.

A gas chromatographic procedure was developed for the determination of methanol in small-volume whole blood samples. Samples (100-200 microliters) were prepared by protein precipitation, with direct injection of the supernatant on a wide-bore capillary column. The recovery of methanol and acetonitrile (the internal standard) was approximately 90% and did not vary with sample volume. The assay was linear from 2 micrograms/ml (the limit of detection) through 1000 micrograms/ml and was highly reproducible (intra-day coefficient of variation less than 2.5%). Assay performance was assessed following exposure of rats to methanol. The results indicate that the present procedure is suitable for studies of methanol disposition in small rodent species.

Animals↗
PubMed1991

Enterohepatic recirculation and renal metabolism of morphine in the rat.

Morphine (2.5 mg/kg) was administered iv to intact (I), bile duct-cannulated (BC), and bile duct-cannulated--renal-ligated (BC-RL) rats (n = 4 per group) to investigate the extent of enterohepatic recirculation and renal metabolism of the drug. A decrease in the serum area under the concentration-time curve (AUC) was observed for the BC in comparison with I rats. From these AUC values, it was determined that approximately 16% of the administered dose was subject to enterohepatic recirculation. In addition, a statistically significant (p less than 0.05) decrease in the systemic clearance of morphine was observed in the BC-RL rats compared with the BC animals (55.2 +/- 17.2 versus 31.4 +/- 8.5 mL/min/kg). This decrement in systemic clearance appeared to be the result of a significant decrease in the formation clearance of morphine glucuronide after ligation of the renal pedicles (23.2 +/- 4.8 versus 10.9 +/- 5.0 mL/min/kg). Renal metabolic clearance was calculated as 15.7 mL/min/kg, accounting for 28.5% of the systemic clearance of morphine. Hepatic clearance (31.4 +/- 8.5 mL/min/kg) accounted for 56.8% of total systemic clearance.

Animals↗
PubMed1991

Physiologic and metabolic influences on enterohepatic recirculation: simulations based upon the disposition of valproic acid in the rat.

The potential influence of alterations in several physiologic processes (hepatocellular egress, biliary excretion, gastrointestinal transit) and biotransformation steps (oxidative metabolism, glucuronidation) on the disposition of agents subject to significant enterohepatic recirculation (ER) via the glucuronide conjugate was examined in a series of simulation experiments. The model of ER developed was based upon the disposition of valproic acid (VPA) and valproate glucuronide (VPA-G) in the rat. The systemic disposition of VPA was simulated following changes in several processes contributing to (or competing with) ER: hepatic oxidative metabolism, hepatic glucuronidation, sinusoidal egress of glucuronide conjugate, canalicular egress of glucuronide conjugate, and gastrointestinal transit. Changes in the formation clearance of VPA-G resulted in a less than proportional change in systemic clearance of VPA, whereas changes in oxidative metabolism led to a greater than proportional change in systemic clearance. Furthermore, alterations in hepatocellular egress of VPA-G affected the disposition of the parent compound, suggesting that drug interactions or disease state effects on metabolite transport may be misinterpreted as effects at the level of metabolite formation. Analytical methods are proposed to recover the intrinsic kinetic parameters (formation clearances of metabolites, renal clearance of parent, volume of distribution) in the presence of ER from the systemic disposition of the parent alone.

Animals↗
PubMed1991

Thermal injury decreases hepatic blood flow and the intrinsic clearance of indocyanine green in the rat.

The influence of severe thermal injury (full-thickness burns involving 50% of the body surface area) on hepatic blood flow in the rat was assessed using the tricarbocyanine dye indocyanine green (ICG). In a randomized crossover fashion, rats received sequential infusions of ICG through both the femoral vein and the portal vein, allowing the estimation of total hepatic plasma clearance and transhepatic extraction of the dye. These two parameters, along with the hematocrit, were used to calculate intrinsic hepatic clearance of ICG and hepatic blood flow. Animals were examined at 0 (control), 0.5, 12, or 24 hr following infliction of scald burns. Hepatic blood flow was decreased significantly by 0.5 hr postburn and remained approximately 20% below normal throughout the remainder of the study. The intrinsic efficiency of the liver in removing ICG from the systemic circulation was also decreased by thermal injury. The potential mechanisms involved in these two physiologic perturbations are discussed.

Animals↗
PubMed1989

Specific assay for the quantitation of indocyanine green in rat plasma using high-performance liquid chromatography with fluorescence detection.

A rapid and sensitive reversed-phase HPLC assay employing fluorescence detection was developed for quantitating indocyanine green (ICG) in rat plasma. Sample preparation entailed precipitation of plasma proteins with acetonitrile prior to injection on the column. The assay was linear from 0.4 to 200 micrograms/mL, with a detection limit of 3 ng on column. The plasma concentration-time profile of ICG was characterized by this HPLC method and compared with the traditional spectrophotometric assay following iv bolus and iv infusion administration of 5 mg/kg of ICG to rats. Concentrations of ICG obtained using the spectrophotometric assay were consistently higher than those determined by HPLC. In animals receiving ICG by infusion, the maximum difference between the two assays was observed 1 min post-infusion and became negligible by 5 min post-infusion. The calculated pharmacokinetic parameters for ICG, systemic clearance and apparent volume of distribution, were higher using the HPLC assay as compared with the spectrophotometric procedure. The data suggest that a biotransformation or degradation product of ICG is formed in the rat and interferes with the determination of ICG by the spectrophotometric assay. Since the HPLC assay is specific for the parent dye, it is suggested that this assay method be used when determining pharmacokinetic parameters of ICG in rats.

Animals↗
PubMed1989

Contribution of metabolites to the route- and time-dependent hepatic effects of di-(2-ethylhexyl)phthalate in the rat.

The effects of exposure to the plasticizer di-(2-ethyl-hexyl)phthalate (DEHP) and its two primary products of presystemic de-esterification, mono-(2-ethylhexyl)phthalate and 2-ethyl-hexanol, on hepatic microsomal oxidation were investigated in rats. The metabolic clearance of antipyrine was utilized as an in vivo measure of the activity of the hepatic microsomal oxidative enzyme system. Subchronic (7 days) p.o. treatment of rats with DEHP, mono-(2-ethylhexyl)phthalate or 2-ethylhexanol produced a substantial increase in both wet liver weight and antipyrine clearance relative to corn oil-treated controls. In contrast, i.p. administration of DEHP resulted in a minor but statistically significant stimulation of liver growth and antipyrine metabolism. Whereas chronic administration of the plasticizer or its metabolites produced apparent induction of hepatic microsomal oxidative enzymes, administration of a single dose of each compound was associated with immediate inhibition of the metabolism of antipyrine. The present data suggest that the products of deesterification of DEHP are primarily responsible for the stimulation of hepatic metabolism observed after long-term exposure to the plasticizer, whereas the parent compound and both metabolites have the potential to produce acute inhibition of hepatic microsomal oxidation in vivo.

Animals↗
PubMed1986

Antipyrine kinetics following partial blood exchange with Fluosol-DA in the rat.

The effects of partial blood exchange with Fluosol-DA on hepatic microsomal oxidative metabolism have been studied in the rat. Antipyrine clearance (Cl) was used as an in-vivo measure of the activity of the mixed function oxidase system. Rats were partially exchanged with Fluosol-DA and dosed with antipyrine at selected time intervals following exchange. No change in antipyrine Cl was observed at 0.5 h, but there was a statistically significant decrease at 24 h and then an increase by more than 50% relative to control at 48 and 72 h. These data indicate that the effects of Fluosol-DA on hepatic function are time-dependent and that Fluosol-DA has the potential both to inhibit and to enhance hepatic metabolism. The possibility of altered hepatic metabolism should be considered when patients transfused with Fluosol-DA are given drugs primarily metabolized by the mixed function oxidase system.

Animals↗
PubMed1985

Effects of route of administration and repetitive dosing on the disposition kinetics of di(2-ethylhexyl) phthalate and its mono-de-esterified metabolite in rats.

The disposition kinetics of the plasticizer di(2-ethylhexyl) phthalate (DEHP) and its biologically active metabolite mono(2-ethylhexyl) phthalate (MEHP) were studied in rats following single or multiple administration of DEHP by various routes. Following a single intraarterial (ia) injection, a large apparent volume of distribution (5390 ml/kg) and a high rate of clearance (21.5 ml/min/kg) were observed for DEHP. The systemic availability of DEHP was low following both single po (13.6%) and ip (5.2%) administration. A marked route-dependency in the formation of MEHP from DEHP was observed. The circulating concentrations of MEHP were substantially higher than those of DEHP (i.e., area under the blood concentration-time curve (AUC) ratio of approximately 7) after po administration, whereas concentrations of the mono-de-esterified metabolite were much lower relative to the parent diester concentration after ia or ip administration (i.e., AUC ratio less than 0.4). Pharmacokinetic calculations revealed that approximately 80% of a po dose of DEHP undergoes mono-de-esterification, as compared to only about 1% of the dose following either ia or ip administration. Hence, the low po systemic availability of DEHP may be largely attributed to presystemic hydrolysis of DEHP to MEHP in the gut, whereas slow and/or incomplete absorption is the likely cause of the poor bioavailability of DEHP after ip administration. No significant accumulation in the circulating concentrations of DEHP or derived MEHP were observed following 7 days of repetitive administration of DEHP. However, multiple ip injections resulted in an apparent decrease in the rate and/or extent of DEHP absorption from the peritoneal cavity, while no significant change in the po absorption of the diester was observed. The striking difference in the MEHP to DEHP AUC ratio between po and ip routes was still evident after multiple dosing. These data suggest that previously reported differences in the biologic effects of DEHP in rodents following different routes of administration may be due to route dependency in the mono-de-esterification of the diester.

Administration, Oral↗
PubMed1985

Circulating concentrations of di(2-ethylhexyl) phthalate and its de-esterified phthalic acid products following plasticizer exposure in patients receiving hemodialysis.

The degree of exposure to the plasticizer di(2-ethylhexyl) phthalate (DEHP) was assessed in 11 patients undergoing maintenance hemodialysis for the treatment of renal failure. The amount of DEHP leached from the dialyzer during a 4-hr dialysis session was estimated by monitoring the DEHP blood concentration gradient across the dialyzer. Circulating concentrations of the biologically active products of DEHP de-esterification, viz., mono(2-ethylhexyl) phthalate (MEHP) and phthalic acid, were also determined during the dialysis session. On the average, an estimated 105 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 23.8 to 360 mg. The rate of extraction of DEHP from the dialyzer was correlated with serum lipid content as expressed by the sum of serum cholesterol and triglyceride concentrations (r = +0.65, p less than 0.05). Time-averaged circulating concentrations of MEHP during dialysis (1.33 +/- 0.58 micrograms/ml) were similar to those of DEHP (1.91 +/- 2.11 micrograms/ml). Blood concentrations of phthalic acid (5.22 +/- 3.94 micrograms/ml) were higher than those of the esters. The length of time patients had been receiving regular dialysis treatment was not a determinant of circulating concentrations of DEHP or MEHP. In contrast, time-averaged circulating concentrations of phthalic acid correlated strongly with the duration (in years) of dialysis treatment (r = +0.92, p less than 0.001). The results indicated substantial exposure to DEHP during hemodialysis and that the de-esterified products of DEHP are present in significant concentrations in the systemic circulation. Further study is needed to assess the contribution of these metabolites to the biological actions of DEHP in man.

Adult↗
PubMed1985

A timed intravenous pentylenetetrazol infusion seizure model for quantitating the anticonvulsant effect of valproic acid in the rat.

A convulsive seizure model that utilizes timed intravenous infusions of pentylenetetrazol (PTZ) was developed to quantitate the magnitude of anticonvulsant effect in individual rats. PTZ was infused through an indwelling jugular vein catheter, and the threshold dose of PTZ was calculated from the time needed to produce clonic convulsions, the body weight of the animal, and the rate of infusion of the convulsant. The threshold dose of PTZ was determined in all animals 48 hr before and 15 min after anticonvulsant treatment. From theoretical considerations, the magnitude of anticonvulsant effect was defined as the logarithm of the posttreatment to pretreatment PTZ threshold dose ratio (log DR). The PTZ threshold was found to be insensitive to the rate of PTZ infusion and the body weight of the animal. Furthermore, the PTZ pretest did not influence the results of the posttest in animals treated with saline, and the interanimal variability in the PTZ threshold was found to be low (coefficient of variation of 12.2%). The PTZ infusion model was tested in a preliminary dose-response study of the anticonvulsant valproic acid (VPA). The ED50 for VPA determined with PTZ infusion technique (76.1 +/- 9.0 mg/kg) was in good agreement with a previous study that used the classical subcutaneous PTZ test. Since anticonvulsant effect is measured in individual, as opposed to groups, of animals, the PTZ infusion procedure may offer distinct advantages in the study of the pharmacodynamics of anticonvulsant compounds.

Animals↗
PubMed1984

High-performance liquid chromatographic procedure for the determination of di-(2-ethylhexyl)phthalate in human blood specimens. Problems of variable-extraction yield and the use of standard addition for calibration.

A high-performance liquid chromatographic procedure was developed for the determination of di-(2-ethylhexyl)phthalate (DEHP) concentrations in human whole blood samples. The solvent extraction of DEHP was found to be highly variable between samples obtained from different subjects (coefficient of variation of 30.4%). The recovery of DEHP following extraction with ethyl acetate was negatively correlated with serum lipid content, as expressed by the sum of serum cholesterol and triglyceride concentrations (r = -0.864). The technique of standard addition of DEHP allowed a single-point calibration of DEHP extractability in individual blood samples, and provided an accurate estimation of DEHP concentration (coefficient of variation of approximately 6% in replicate samples). The potential for intersample variability in the solvent extraction of other highly lipid-soluble compounds should be considered.

Chromatography, High Pressure Liquid↗
PubMed1984

Effect of renal failure and bis(2-ethylhexyl) phthalate pretreatment on the disposition and metabolism of antipyrine in the rat.

Renal failure patients undergoing hemodialysis are regularly exposed to phthalate plasticizers leached from dialysis tubings. Previous studies have shown that antipyrine is eliminated more rapidly in chronic renal failure patients compared with normal individuals. Therefore, the effect of bis(2-ethylhexyl) phthalate on the metabolism of antipyrine was investigated in normal and renal failure rats. In normal animals, the elimination kinetics of an intravenous dose of antipyrine (20 mg/kg) was determined before and after 14 days of peroral treatment with 2 mL/kg/d of bis(2-ethylhexyl) phthalate. The plasma clearance of antipyrine increased markedly after bis(2-ethylhexyl) phthalate treatment. There was a corresponding decrease in the elimination half-life of antipyrine, whereas the apparent volume of distribution was not affected. Both liver weight and hepatic cytochrome P450 content increased following exposure to bis(2-ethylhexyl) phthalate, indicating the induction of hepatic microsomal enzymes. The fractional urinary recovery of the N-demethyl, 4-hydroxy, and 3-hydroxymethyl metabolites of antipyrine was not altered, suggesting that all three oxidative pathways were induced to the same extent. Renal failure alone did not affect the elimination kinetics of antipyrine. However, antipyrine clearance was induced to a greater extent by bis(2-ethylhexyl) phthalate treatment in the renal failure rats as compared with the control animals. The potential for phthalate plasticizers to alter hepatic drug metabolism in hemodialysis patients should be considered.

Animals↗
PubMed1984

Dose-dependent pharmacokinetics of antipyrine in the rat.

In rats given a single intravenous dose, the disposition of antipyrine was dose-dependent and followed apparent first-order kinetics only at the lowest (20 mg/kg) dose administered. The initial rate of disposition decreased with increasing dose, indicating apparent saturation of antipyrine metabolism. The observed nonlinearity was unusual in that the terminal elimination rate increased significantly with increasing dose, suggesting that autoinduction of metabolism may occur after a single exposure to antipyrine. The potential implications of dose-dependent antipyrine pharmacokinetics for the use of antipyrine as a model substrate in the estimation of hepatic microsomal oxidative enzyme activity are discussed.

Animals↗
PubMedDate not supplied

Central nervous system uptake kinetics of pentylenetetrazol in the developing rat.

The present investigation was undertaken to examine the brain uptake kinetics of the central nervous system (CNS) stimulant pentylenetetrazol (PTZ) during postnatal development. This study represents part of an ongoing effort to develop an appropriate seizure model for investigations of anticonvulsant action in the developing rat. The systemic pharmacokinetics of PTZ were examined in male and female adult animals following both intravenous (IV) and subcutaneous (SC) injection. PTZ administered SC was absorbed rapidly and was completely bioavailable in both genders. No statistically significant gender-dependent differences in the disposition of PTZ were identified. To examine the CNS uptake kinetics of PTZ, animals of four different age groups (5, 10, 20, and 60 days postnatal) received timed SC infusions of PTZ. Significant age-related differences in the rate of uptake of PTZ into the CNS were observed. These differences paralleled the previously reported age-dependent changes in the dose of PTZ required to elicit seizure activity. The results of this investigation indicate that the apparent age-related change in sensitivity to the convulsant effects of PTZ is due in part to age-dependent uptake of the convulsant into brain tissue.

Aging↗