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K L Brouwer

Publications and source records attributed to K L Brouwer.

72 records · Page 4Linked to original sources
PubMed1989

Alpha 1-acid glycoprotein high-performance liquid chromatography column (EnantioPAC) as a screening tool for protein binding.

An attempt was made to correlate retention behavior on a high-performance liquid chromatographic (HPLC) system employing an immobilized alpha 1-acid glycoprotein (AAG) column with AAG binding behavior for various compounds. Protein binding was assessed by propranolol displacement studies in an equilibrium dialysis system using isolated AAG. HPLC retention behavior poorly correlated with propranolol displacement from AAG. This system is not suitable for use as a screening tool for AAG affinity.

Chromatography, High Pressure Liquid↗
PubMed1987

Multiple carriers for uptake of [3H]estradiol-17 beta(beta-D-glucuronide) in isolated rat hepatocytes.

The transport of the cholestatic steroid glucuronide, 3H-estradiol-17 beta-(beta-D-glucuronide) (E2 17G), was examined in isolated female rat hepatocytes over a broad substrate concentration range (0.1-100 microM). Two different carrier systems were identified with the following kinetic parameters: Km1 = 4.54 microM; Vmax1 = 0.149 nmol/min/mg protein; Km2 = 149 microM; Vmax2 = 0.641 nmol/min/mg protein. Taurocholate and testosterone glucuronide selectively and competitively inhibited [3H]-E2 17G uptake at the high affinity site. Ki values calculated for taurocholate (43 microM) and testosterone glucuronide (28 microM) indicated that these two inhibitors were relatively weak competitors for this E2 17G transport site. Conversely, E2 17G inhibited [3H]taurocholate uptake into isolated hepatocytes (Ki = 43 microM). Bromosulfophthalein (10 microM) inhibited uptake of 0.5-50 microM [3H]-E2 17G by 55-85%, whereas morphine glucuronide (100 microM) had no significant effect on uptake of [3H]-E2 17G at these concentrations. The effects of taurocholate, testosterone glucuronide, bromosulfophthalein, and morphine glucuronide on [3H]-E2 17G uptake into isolated rat hepatocytes correlated with the ability of these agents to inhibit binding of [3H]-E2 17G to specific sites in rat liver plasma membranes. These data support the postulate that the two [3H]-E2 17G binding sites identified in female rat liver plasma membranes represent two distinct organic anion carriers and indicate that the high affinity site for [3H]-E2 17G represents a carrier that is shared by organic anions and bile acids.

Animals↗
PubMed1985

Effects of phenobarbital and SKF-525A on in vitro hepatic metabolism of verapamil and nifedipine.

Both verapamil and nifedipine are first-generation calcium-entry antagonist drugs which are eliminated by hepatic metabolism. To evaluate the effects of enzyme induction and suppression on the biotransformation of these compounds, liver homogenate fractions were prepared from male Fisher (F344) rats, which were either untreated, or injected intraperitoneally with phenobarbital or with SKF-525A prior to sacrifice. Known concentrations of verapamil or nifedipine were incubated with the 9,000 g supernatant, and the quantity of unchanged drug remaining after 10 min was measured. SKF-525A pretreatment significantly decreased the elimination (disappearance) rate of both calcium-entry antagonist compounds. Phenobarbital increased the rate of disappearance of verapamil, but had no effect on that of nifedipine. Difference spectra of hepatic microsomes to which verapamil had been added revealed a concentration-dependent, saturable interaction between drug and enzymes with spectral changes characteristic of "type I' substrates for cytochrome P-450 monooxygenase(s). The spectral characteristic of microsomes to which nifedipine was added could not be determined because of drug absorption at 350-500 nm. These data imply that verapamil metabolism is mediated by the cytochrome P-450 monooxygenase(s), and that nifedipine metabolism likely involves hepatic enzyme systems other than those known to be induced by phenobarbital.

Animals↗
PubMed1985

Effect of hypoxia and pregnancy on antipyrine metabolism in isolated perfused rat livers.

The effect of hypoxia on antipyrine metabolism was studied in isolated perfused livers from pregnant (19-21 days gestation) and nonpregnant female Wistar rats. Hypoxia was induced by altering the blood content and/or flow rate of the recirculating perfusion medium. Inflow and outflow pO2 values, in themselves, were not valid indicators of oxygen delivery and consumption when the liver was perfused with a blood containing medium. At a given oxygen delivery rate, oxygen consumption per gram of liver was the same in nonpregnant and pregnant rat livers. The absolute clearance of antipyrine (milliliters per hour) was significantly greater in livers from pregnant compared to nonpregnant rats, whereas antipyrine clearance, corrected for liver weight (milliliters per hour gram of liver), was significantly lower in pregnant rat livers. Antipyrine clearance (milliliters per hour) was linearly related to oxygen consumption (milliliters per minute or micromoles per minute per gram of liver) in both the nonpregnant and pregnant rat livers. As oxygen consumption decreased, livers from pregnant rats maintained a greater ability to clear antipyrine than livers from nonpregnant rats. This study emphasizes the importance of maintaining adequate oxygen delivery to isolated perfused livers during drug metabolism studies to ensure constant oxygen consumption. Otherwise, alterations in the flow rate or hematocrit of the perfusion medium may directly alter the elimination rate of the substrate.

Animals↗
PubMed1984

Phenobarbital in the genetically obese Zucker rat. I. Pharmacokinetics after acute and chronic administration.

The pharmacokinetics of the enzyme inducer, phenobarbital, was evaluated in genetically obese and lean Zucker and lean Sprague-Dawley rats. The volume of distribution of phenobarbital in obese Zucker rats was larger (0.416 liter) than for lean Zucker (0.299 liter) or Sprague-Dawley rats (0.312 liter). Standardizing the volume of distribution for total body weight in the obese and lean Zucker and lean Sprague-Dawley rats resulted in similar volume terms. Intra- and inter-strain differences in phenobarbital clearance were observed between the obese and lean Zucker (11.9 and 14.1 ml/hr, respectively) and lean Sprague-Dawley rats (23.0 ml/hr). Greater differences in phenobarbital clearance were observed when clearance was corrected for body weight. Whether comparing the absolute or standardized pharmacokinetic data, lean and obese Zucker rats will exhibit 2- to 3-fold higher phenobarbital plasma concentrations after administration of a standard 75- to 100-mg/kg enzyme-inducing regimen relative to Sprague-Dawley rats. Pharmacokinetic parameters from the single dose study were used to calculate appropriate phenobarbital doses (21-58 mg/kg/12 hr) to achieve similar steady-state phenobarbital plasma concentrations after chronic oral administration in all three groups of rats. Steady-state phenobarbital clearance values were not significantly different from clearance values after single dose administration in each group of rats. The dramatic intra- and inter-strain alterations in phenobarbital disposition demonstrated in this study explain the high mortality reported in Zucker rats after administration of traditional enzyme induction doses of phenobarbital. Differences in phenobarbital disposition should be considered in enzyme induction studies.

Animals↗
PubMed1984

Phenobarbital in the genetically obese Zucker rat. II. In vivo and in vitro assessments of microsomal enzyme induction.

In vivo and in vitro alterations in drug metabolism and the extent of enzyme induction of the hepatic microsomal cytochrome P-450 system were evaluated in obese and lean Zucker and lean Sprague-Dawley rats. Phenobarbital enzyme-inducing regimens were administered p.o. to achieve similar steady-state phenobarbital plasma concentrations. Control rats received p.o. placebo solution. No significant intra- or inter-strain differences in antipyrine clearance (milliliters per hour) or apparent volume of distribution (liters) were observed between the placebo-treated lean Sprague-Dawley, lean Zucker and obese Zucker rats. Intra- and inter-strain differences in hepatic microsomal protein and cytochrome P-450 content were observed. Compared to placebo, antipyrine clearance (milliliters per hour) after chronic phenobarbital pretreatment was increased in the Sprague-Dawley (198%) and lean Zucker rats (131%), but not significantly altered in the obese Zucker rats. Similarly, increases in hepatic weight, whole liver microsomal protein and cytochrome P-450 content were also observed in the Sprague-Dawley (34, 124 and 352%, respectively) and the lean Zucker rats (24, 96 and 249%, respectively). However, no significant alterations in these parameters were observed in the obese Zucker rats after phenobarbital treatment. Results from these in vivo and in vitro studies implicate alterations in drug metabolism and genetic differences in cytochrome P-450 content in Zucker rats relative to the Sprague-Dawley strain. Obese Zucker rats failed to exhibit a significant induction response after phenobarbital pretreatment.

Animals↗
PubMedDate not supplied

Venous irritation related to intravenous administration of phenytoin versus fosphenytoin.

STUDY OBJECTIVE: To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug. DESIGN: Randomized, double-blind, two-period, crossover study. SETTING: University hospital clinical research unit. PATIENTS: Twelve healthy volunteers within 15% of ideal body weight and with no clinically significant abnormalities on physical examination, medical history, or laboratory assessment. INTERVENTIONS: Volunteers randomly received a 30-minute infusion of phenytoin sodium 250 mg (250 mg/5 ml) or an equimolar dose of fosphenytoin 375 mg (375 mg/5 ml). Subjects returned for the crossover treatment 14-21 days later. MEASUREMENTS AND MAIN RESULTS: Subjects assessed venous irritation (pain, burning, itching), and investigators evaluated phlebitis (erythema, swelling, tenderness), induration, exudation, and cording. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in eight subjects (p < 0.05); cording occurred in six subjects. The time course of phenytoin-induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hours. Cording was first noted between 24 hours and 1 week after infusion. In contrast, fosphenytoin was associated with mild pain in two subjects, one incident of phlebitis, and no erythema or cording. CONCLUSIONS: Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. The clinical use of this water-soluble phenytoin prodrug should minimize the frequency and severity of infusion-site reactions and should allow convenient, rapid, intravenous administration of drug, undiluted or admixed with intravenous solutions.

Adolescent↗
PubMedDate not supplied

Intravenous epoprostenol sodium does not increase hepatic microsomal enzyme activity in rats.

Previous studies have indicated that epoprostenol may increase hepatic microsomal enzyme activity both in animals and humans. However, interpretation of the results of these studies may be confounded by the route of epoprostenol administration or small sample sizes. The primary objective of the present investigation was to evaluate the effects of epoprostenol (given as a continuous intravenous infusion) on hepatic microsomal enzyme activity in rats. Male Sprague Dawley rats (220-290 g) received infusions of either vehicle (glycine buffer, 1 mL/hr) or 0.2 microgram/kg/min epoprostenol through a jugular vein cannula for 24 hr or 7 days. At the end of the infusion, a 25 mg/kg i.v. bolus of antipyrine was administered and blood samples were collected over 6 hr. Serum antipyrine concentrations were determined by HPLC. Twenty-four hr post-infusion, hepatic microsomes were prepared, and cytochrome P-450 content was determined by difference spectroscopy. Cytochrome P-450 content and antipyrine clearance values determined from serum antipyrine concentration-time profiles were not significantly different between treatment groups. Antipyrine clearance [mean (SD)] in the 24-hr vehicle-treated group was 3.68 (0.49) mL/min/kg versus 4.35 (1.1)mL/min/kg in the epoprostenol-treated group. In the 7-day vehicle-treated rats, antipyrine clearance was 5.43 (1.0) mL/min/kg compared to 4.68 (0.61) mL/min/kg in epoprostenol-treated rats. A statistically significant effect of infusion duration was observed in the control group, i.e., antipyrine clearance in rats treated with vehicle for 7 days was significantly greater than that observed in rats treated with vehicle for 24 hr. However, the increase was less than 50%. These data suggest that when epoprostenol is administered as an intravenous infusion to rats, no significant alterations in hepatic microsomal enzyme activity occur. Based on these data, long term changes in hepatic metabolism in response to chronic epoprostenol administration are not expected.

Animals↗
PubMedDate not supplied

Absolute bioavailability of phenytoin after 3-phosphoryloxymethyl phenytoin disodium (ACC-9653) administration to humans.

3-Phosphoryloxymethyl phenytoin disodium (ACC-9653) is a water-soluble investigational phenytoin (PHT) prodrug for parenteral administration. The objectives of this investigation were to determine the absolute bioavailability and free fraction of PHT after intravenous (i.v.) administration of ACC-9653. Twelve healthy male volunteers received PHT sodium (250 mg/5 ml; 229.95 mg free acid) and ACC-9653 (375 mg/5 ml; 232.87 mg free acid) i.v. in 30 min in a randomized, double-blind cross-over fashion. The conversion half-life (t 1/2) of ACC-9653 to PHT was 9.3 +/- 2.7 min. ACC-9653 was not detected in urine and greater than 99% of ACC-9653 was converted to PHT. The PHT area under the curve (AUC) was not statistically different between treatments; the bioavailability of PHT after ACC-9653 was 99 +/- 11%. The fraction of unbound converted PHT at the end of the prodrug infusion, in the presence of 44 micrograms/ml ACC-9653, was significantly higher than at 180 min, when the concentration of ACC-9653 was 0.1 microgram/ml. ACC-9653 was shown to be a bioequivalent PHT prodrug exhibiting less irritation at the injection site than the current marketed PHT.

Biological Availability↗
PubMedDate not supplied

Correlation of delayed peak concentration with infusion-site irritation following diazepam administration.

Diazepam 10 mg/2 mL iv was administered undiluted over five minutes to nine healthy men on two separate occasions. The infusion site was evaluated before and after each infusion by subject assessment of pain on a severity scale of zero (none) to ten (most). Blood samples were collected at 0, 5, 20, 30, 45, and 60 minutes, and periodically for 72 hours postinfusion. Diazepam plasma concentrations were determined by HPLC. Concentrations at five minutes (end of infusion) ranged from 0 to 889 ng/mL. Maximum plasma concentration (Cmax) was observed at 5 minutes for 10 treatments, at 20 minutes for 7 treatments, and at 30 minutes for 1 treatment. The observed Cmax ranged from 221 to 889 ng/mL. When time to reach peak plasma concentration (tmax) was 5 minutes, the Cmax was significantly greater than when tmax was 20 minutes (670 +/- 87 vs. 267 +/- 40 ng/mL, p less than 0.005). The area under the curve did not differ significantly between these two groups. The pain score at the end of infusion ranged from zero to five and was inversely related to the concentration at five minutes (r2 = 0.45, p = 0.002). The association between venous irritation, a low plasma concentration at the end of the infusion, and a delayed Cmax suggests that diazepam precipitated in the vein.

Adult↗
PubMedDate not supplied

Probenecid-impaired biliary excretion of acetaminophen glucuronide and sulfate in the rat.

Acetaminophen (APAP; 100 mg/kg iv) and probenecid (50 mg/kg bolus + 11.4 mg/hr/kg infusion) were administered to male Sprague-Dawley rats to examine the disposition of APAP, and its glucuronide (AG) and sulfate (AS) conjugates in plasma, bile, and urine. Probenecid significantly decreased the formation clearance of AG from 3.65 +/- 0.434 to 1.94 +/- 0.441 ml/min/kg and the renal clearance of AS from 9.32 +/- 2.26 to 3.15 +/- 1.21 ml/min/kg. The biliary excretion of AG was reduced approximately 3- to 4-fold by probenecid, from 6.54 to 1.87% of the APAP dose, and the AG biliary excretion rate was decreased 4- to 5-fold during probenecid treatment. The more extensive impairment of AG biliary excretion relative to AG formation suggests that probenecid may inhibit the hepatobiliary transport of AG. The significant reduction in the biliary excretion rate at early time points for AS suggests that probenecid may inhibit hepatic AS transport. The study results indicate that probenecid impairs AG and AS formation, AS renal secretion, and AG and AS biliary excretion.

Acetaminophen↗
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

Phenacetin and acetaminophen metabolism in the isolated perfused rat liver. Precursor concentration influences the selection of kinetic parameters to assess hypoxic impairment.

Subnormal oxygen concentrations affect a host of cellular functions and can exist under normal or pathological conditions. The present study examined the effects of hypoxia on phenacetin O-deethylation by the mixed-function oxidase system and the subsequent sulfation and glucuronidation of the generated metabolite acetaminophen, compared to hypoxic alterations in conjugation of administered acetaminophen, in isolated perfused rat livers. A recirculating perfusion system containing either 20% (normoxic conditions) or 2.5% (hypoxic conditions) donor rat blood delivered 4.46 and 1.47 mumol/min/g liver oxygen, respectively, resulting in a 44% reduction in oxygen consumption during hypoxia. The total hepatic clearance of phenacetin was diminished significantly during hypoxia, due to a 60% decrease in the formation clearance of acetaminophen. Hypoxia did not influence significantly the total hepatic clearance of either administered or generated acetaminophen. Although the formation clearance for acetaminophen sulfate (AS) remained unchanged, the Vmax for sulfate formation was diminished 35%. The formation clearance (mean +/- SD; N = 4/group) of acetaminophen glucuronide (AG) was greater from administered compared to generated acetaminophen during normoxia (0.47 +/- 0.15 vs. 0.22 +/- 0.06 ml/min, p less than 0.05), and was decreased 2- to 3-fold during hypoxia (0.14 +/- 0.08 vs. 0.11 +/- 0.07 ml/min). Hypoxic conditions did not affect differentially the time lag for the appearance of AG in perfusate, and did not appear to alter the diffusional barrier for AS and AG from perfusate into the hepatocyte.

Acetaminophen↗
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

Acute phenobarbital administration alters the disposition of acetaminophen metabolites in the rat.

The effects of acute phenobarbital (PB) administration on the disposition of acetaminophen (APAP), acetaminophen glucuronide (AG), and acetaminophen sulfate (AS) were examined in serum, bile, and urine of rats after a 100 mg/kg iv bolus dose of APAP. PB was administered intravenously as either an acute low (12 mg/kg) or high (60 mg/kg) dose to achieve PB serum concentrations equivalent to, or 5-fold higher than, PB concentrations in previous studies where impaired biliary excretion of AG and AS was noted after PB pretreatment for 5 days. Acute high-dose PB administration decreased the formation clearance of AG by 36% (from 3.14 +/- 0.64 to 2.00 +/- 0.70 ml/min/kg), resulting in a significant decrease in the percentage of the dose recovered in urine as AG. Decreased urinary recovery of AS after acute high-dose PB administration was due to an approximate 50% reduction in the renal clearance of AS (from 10.5 +/- 2.1 to 5.44 +/- 2.95 ml/min/kg). Although acute PB administration did not impair the biliary excretion of APAP or AS to a statistically significant extent, there was a trend toward decreased biliary excretion of AG. Large interanimal variability in AG biliary excretion was noted in rats receiving acute PB. These data indicate that serum PB concentrations are not related directly to impaired biliary excretion of AG or AS, and suggest that some other factor is responsible for the inhibition of AG and AS excretion at canalicular transport sites after PB pretreatment.

Acetaminophen↗
PubMedDate not supplied

Bile flow but not enterohepatic recirculation influences the pharmacokinetics of ranitidine in the rat.

Secondary peaks in oral concentration-time profiles following ranitidine administration may be due to discontinuous absorption along the gastrointestinal tract, postabsorptive storage and release, and/or enterohepatic recirculation (ER). The suitability of the rat as an animal model for studying mechanisms of the double peaks, and the relationship between ER and the occurrence of secondary peaks in ranitidine concentration-time profiles, were examined in the present investigation. Male Sprague-Dawley rats received ranitidine by oral gavage (50 mg/kg), and blood was collected at various times for 6 hr after dosing. Eight rats with chronic bile duct and jugular vein cannulae received ranitidine with bile flow intact or interrupted in a randomized complete cross-over design. Bile duct-cannulated (BDC) rats were divided into two groups: four rats received ranitidine immediately after bile flow interruption, and four rats received ranitidine 3 hr after bile flow interruption. Blood and bile were analyzed for ranitidine by HPLC. The area under the ranitidine concentration-time profile, the maximum serum ranitidine concentration, the time of maximum concentration, the fraction of ranitidine absorbed at each blood sample, biliary clearance, and the percentage of the dose recovered in bile as ranitidine were determined. Results indicated that the rat is an appropriate model for studying mechanisms responsible for the double peaking phenomenon. Multiple peaks or plateaus were observed in the ranitidine concentration-time profiles of all rats after oral administration with bile flow intact. Secondary peaks were evident in only two concentration-time profiles of BDC rats when bile flow was interrupted. Less than 3% of the dose was recovered in the bile as ranitidine or metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗