Biomedical subjects

K L Brouwer

Publications and source records attributed to K L Brouwer.

At least 55 records · Page 3Linked to original sources

PubMed1995

Regional gastrointestinal absorption of ranitidine in the rat.

PURPOSE: Ranitidine absorption from isolated segments of rat small intestine (duodenum, midgut, and terminal ileum) was investigated to examine the influence of pH and 50% bile, and to determine if ranitidine is absorbed preferentially from a specific region. METHODS: Ranitidine (50 mg/kg) was administered into each segment in pH 5 or pH 7 buffer, or in 50% bile. Venous blood was collected at various times for 40 min from the right jugular vein. RESULTS: When ranitidine was administered in pH 7 buffer or in 50% bile, Cmax and AUC0-40 were significantly greater after administration into the terminal ileum compared to the duodenum and midgut. AUC0-40 was significantly greater when ranitidine was administered in pH 5 buffer or in 50% bile into the duodenum compared to the midgut. Cmax was significantly different between administration into the duodenum and midgut only when ranitidine was administered in 50% bile. Ranitidine administration in pH 5 buffer significantly decreased AUC0-40 and Cmax after administration into the midgut, and AUC0-40 after administration into the terminal ileum compared to administration with pH 7 buffer or in 50% bile. Bile had no significant effect on AUC0-40 after ranitidine administration into the duodenum and midgut compared to administration in pH 7 buffer. However, bile significantly increased AUC0-40 and Cmax after ranitidine administration into the terminal ileum compared to administration with pH 7 and pH 5 buffer. CONCLUSIONS: Results suggest that ranitidine is absorbed from the entire small intestine. However, the terminal ileum is the optimal site of gastrointestinal absorption. Furthermore, bile enhances ranitidine absorption from the terminal ileum.

Animals↗

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

Radiolabeling of methylphosphonate and phosphorothioate oligonucleotides and evaluation of their transport in everted rat jejunum sacs.

PURPOSE: The therapeutic use of antisense oligonucleotides will likely involve their administration over protracted periods of time. The oral route of drug dosing offers many advantages over other possible routes when chronic drug administration is necessary. However, little is known about the potential for oligonucleotide uptake from the gastrointestinal tract. This issue is addressed in the current work. METHODS: We have developed a simple procedure for radiolabeling oligonucleotides by reductive alkylation with 14C-formaldehyde. We have utilized this approach, as well as 5' addition of fluorophores, to prepare labeled methylphosphonate and phosphorothioate oligonucleotides for use in intestinal transport studies. An everted rat gut sac model was employed to compare the transport of oligonucleotides to that of model compounds whose permeation properties are better understood. RESULTS: We demonstrate that both methylphosphonate and phosphorothioate oligonucleotides are passively transported across the intestinal epithelium, probably by a paracellular route. The rates of transport for both types of oligonucleotides were similar, and were significantly greater than that of the very high MW polymer blue dextran, but were lower than the transport rate of valproic acid, a low MW compound known to have high oral availability. CONCLUSIONS: A significant degree of permeation of oligonucleotides across the gastrointestinal epithelium does occur, but it is still unclear whether this is sufficient to permit effective oral administration of oligonucleotides as drugs.

Alkylation↗

PubMed1995

High-performance liquid chromatographic evaluation of the effect of heat treatment on trimethoprim and sulfamethoxazole stability in serum.

Heat treatment of patient samples is utilized as a method to decrease the risk of accidental transmission of human immunodeficiency virus (HIV). Heat treatment has been reported to affect the outcome of drug analysis. In this study, the effects of heat treatment (56 degrees C for 5 h) and storage for 2 months at -20 degrees C on the stability of trimethoprim (TMP) and sulfamethoxazole (SMX) at three different concentrations in serum (10/100, 1/20, and 0.1/5 microgram/mL) each were evaluated. Simultaneous determination of TMP, SMX, and sulfamethazine (SMeth), the internal standard, in serum was performed by a reversed-phase high-performance liquid chromatographic (HPLC) procedure with isocratic elution and ultraviolet detection. The peak/height ratios (PHRs) for each sample from untreated and heat-treated groups were compared. No statistically significant differences were found between untreated and heat-treated groups for TMP. Heat treatment decreased the PHR for SMX at 100 micrograms/ml concentration (p = 0.042) and increased the PHR for SMX at 20 micrograms/ml concentration (p = 0.049). These marginal differences are unlikely to be significant. Storage of samples for 2 months at -20 degrees C had no statistically significant effect on sample PHRs. Thus, heat treatment of serum does not alter clinical interpretation of TMP and SMX at clinically relevant concentrations and may protect laboratory workers from accidental HIV exposure.

Anti-Infective Agents↗

PubMed1995

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062).

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over a 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 +/- 192 ng.h/ml), maximum concentration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/- 1,222 ng.h/ml) and maximum concentration of drug in serum (5,220 +/- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 +/- 0.15 in HIV-infected patients with hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy-proven cirrhosis, our results suggest that ZDV, could accumulate in HIV-infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

Administration, Oral↗

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↗

PubMed1994

Effects of probenecid on the pharmacokinetics and pharmacodynamics of adinazolam in humans.

The effects of probenecid (2 gm) on the pharmacokinetics, pharmacodynamics, and uricosuric effects of adinazolam and N-desmethyladinazolam were assessed after single dose administration of adinazolam mesylate sustained-release tablets (60 mg) in a randomized, four-way crossover, double-blind study involving 16 healthy male volunteers. Probenecid decreased adinazolam oral clearance, renal N-desmethyladinazolam clearance, and the amount of N-desmethyladinazolam excreted in the urine. Probenecid increased the N-desmethyladinazolam/adinazolam AUC ratio, adinazolam maximum concentration (Cmax), N-desmethyladinazolam Cmax, and N-desmethyladinazolam time to reach Cmax. Uric acid renal clearance was increased significantly by adinazolam or probenecid administration compared with placebo; however, coadministration of adinazolam plus probenecid had no additive effect on uric acid clearance. Psychomotor performance was decreased in the adinazolam plus probenecid treatment compared with the adinazolam treatment. Probenecid potentiated the psychomotor effects of adinazolam after coadministration of the compounds, predominantly because of alterations in N-desmethyladinazolam pharmacokinetics. Therefore the adinazolam dose may need to be reduced when coadministered with probenecid.

Administration, Oral↗

PubMed1993

Hepatic disposition of acetaminophen and metabolites. Pharmacokinetic modeling, protein binding and subcellular distribution.

Successful pharmacokinetic modeling often requires the ability of a simple model to describe a complex series of physiological processes. However, a simple model may be inappropriate. Physiologically-relevant modeling may offer a more appropriate description, but requires further support from in vitro/in vivo data. A well-stirred hepatic model with linear processes was proposed to describe in vivo disposition of acetaminophen and metabolites after a 100 mg/kg bolus of acetaminophen to vehicle- or phenobarbital-pretreated, renal-ligated rats. Model simulations underpredicted acetaminophen glucuronide (AG) concentrations at early time points in serum, and were inconsistent with AG biliary excretion-rate profiles. Intracellular binding of AG by ligandin was hypothesized, and a cytosolic compartment with reversible binding was incorporated into the model. In this second model, only AG bound in the cytosolic compartment was available for excretion into bile. Model 2 better described the AG biliary excretion rate-time profiles based on calculated Akaike's information criterion values. However, no apparent change was observed in the underprediction of AG serum concentrations. Parameter estimates derived from the two models also were different. The rate constants regulating AG formation and sinusoidal egress were increased significantly after phenobarbital pretreatment according to model 1, while the AG biliary excretion rate constant was decreased significantly. Parameter estimates based on model 2 suggested that phenobarbital pretreatment impaired the cytosolic binding of AG but increased significantly the AG biliary excretion rate constant. The physiologic relevance of model 2 was not supported by a subsequent investigation of the protein binding and subcellular distribution of acetaminophen and metabolites. Acetaminophen, AG and acetaminophen sulfate (AS) were not bound extensively in hepatic cytosol (mean +/- SD unbound fractions were 0.90 +/- 0.08, 0.97 +/- 0.08, and 0.88 +/- 0.06, respectively). Phenobarbital pretreatment did not alter significantly the unbound fractions of acetaminophen, AG or AS in hepatic cytosol. Acetaminophen was distributed to a greater extent in lysosomes than in the nuclear, mitochondrial, microsomal and cytosolic fractions. Distribution of AS predominated in cytosolic and lysosomal fractions. AG was detected only in cytosol. Phenobarbital pretreatment decreased the content of acetaminophen, AG and AS in all hepatic fractions. This study demonstrates the utility of pharmacokinetic modeling in exploring mechanistic hypotheses. However, these results underscore the importance of obtaining pivotal data from in vitro/in vivo studies to validate hypothesized mechanisms.

Acetaminophen↗

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

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

Effect of phenobarbital and p-hydroxyphenobarbital glucuronide on acetaminophen metabolites in isolated rat hepatocytes: use of a kinetic model to examine the rates of formation and egress.

Conventional analysis of initial uptake and egress rates in isolated hepatocytes is limited in the ability to distinguish between rates of metabolite formation and egress, and to separate basolateral and canalicular transport processes. The present study examined the applicability of kinetic modeling in describing acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) formation and egress in hepatocytes after acute exposure to phenobarbital or p-hydroxyphenobarbital glucuronide (p-OHPBG) in vitro, or in vivo phenobarbital pretreatment. A significant pretreatment effect on AG and AS disposition was seen based on initial rates of egress. In vivo phenobarbital pretreatment decreased the initial egress rate of AG compared to vehicle pretreatment, and the initial egress rate of AS compared to all other treatments. A pharmacokinetic model incorporating AG and AS formation in hepatocytes as well as egress processes (including diffusional and active transport components) was fit to the data. Parameter estimates derived from model fits to the data showed the expected increase in acetaminophen glucuronidation and decrease in sulfation after phenobarbital pretreatment; in addition, an increase in the AG diffusional rate constant and a decrease in the AS diffusional rate constant was apparent. The excretion Vmax for AG was decreased statistically after acute phenobarbital exposure in vitro, and in vivo phenobarbital pretreatment, with a concomitant statistical increase in the Km for AG excretion. In vitro acute p-OHPBG exposure also decreased significantly the excretion Vmax for AG. These data are consistent with the hypothesis that phenobarbital-impaired biliary excretion of AG is a function of impaired canalicular transport due to the presence of p-OHPBG. They further suggest that the mechanism may not be simple competitive inhibition. This work demonstrates the utility of a kinetic modeling approach to differentiate metabolic and transport processes when analyzing data from isolated hepatocyte studies. Additional information may be gained that would not be apparent by conventional methods of analysis.

Acetaminophen↗

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↗

PubMed1992

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.

Adult↗

PubMed1992

Impaired biliary excretion of acetaminophen glucuronide in the isolated perfused rat liver after acute phenobarbital treatment and in vivo phenobarbital pretreatment.

The influence of phenobarbital (PB) on the hepatobiliary disposition of acetaminophen (APAP), acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) was examined in the recirculating isolated perfused rat liver (IPL). PB was administered as a 5-mumol bolus to the IPL (acute) or in vivo (75 mg/kg/day, i.p., x 5 days), followed by a 48-hr washout, before addition of an APAP (66-mumol) bolus to the IPL. Acute PB administration to the IPL did not affect the total hepatic clearance of APAP or the formation clearance to AG and AS. The rate constant for the biliary excretion of AG and the percentage of the dose recovered in bile as AG were decreased significantly after the acute PB dose. In vivo PB pretreatment induced significantly the UDP-glucuronyltransferases (i.e., an increase in APAP clearance, the formation clearance to AG and in the estimate of the AG formation rate constant). The estimate of the AG sinusoidal egress rate constant after in vivo PB pretreatment also was increased significantly. The AG biliary excretion rate constant and the percentage of the dose recovered in bile as AG were decreased approximately 5-fold after in vivo PB pretreatment, similar to values obtained after acute PB administration. PB was detected only after acute PB administration, whereas unconjugated p-hydroxyphenobarbital was not detected after either treatment. These data indicate that neither PB itself nor an induction effect related to in vivo PB pretreatment are required directly to impair hepatobiliary disposition.

Acetaminophen↗

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↗

PubMed1990

Evaluation of the pharmacokinetic interaction between diazepam and ACC-9653 (a phenytoin prodrug) in healthy male volunteers.

The protein binding and pharmacokinetics of diazepam, ACC-9653 (a phenytoin prodrug), and phenytoin were evaluated in nine healthy male volunteers following administration of diazepam and ACC-9653, alone or concomitantly, in a randomized crossover design. No significant differences were observed in the fraction unbound or pharmacokinetic parameters of ACC-9653, phenytoin, or diazepam when ACC-9653 was administered alone compared to concomitant administration with diazepam. The phenytoin fraction unbound increased significantly with increased concentrations of ACC-9653, indicating displacement of phenytoin from its binding sites by ACC-9653. ACC-9653 also demonstrated concentration dependent binding. The lack of a significant pharmacokinetic drug interaction between ACC-9653 and diazepam suggests that these drugs may be safely administered together, although this conclusion should be confirmed in the intended patient population.

Adult↗

PubMed1990

Altered hepatobiliary disposition of acetaminophen metabolites after phenobarbital pretreatment and renal ligation: evidence for impaired biliary excretion and a diffusional barrier.

The effects of phenobarbital (Pb)-pretreatment and bilateral renal ligation on the disposition of acetaminophen, acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were examined in serum, bile and urine of rats. Pb-pretreatment significantly decreased the percentage of the acetaminophen dose (100 mg/kg) excreted in bile as the glucuronide and sulfate conjugates in rats with intact kidneys [AG (0.94% vs. 6.49%); AS (1.41% vs. 4.19%)] and in renal-ligated rats [AG (2.22% vs. 7.71%); AS (6.12% vs. 9.13%)], compared to vehicle-pretreated controls. Decreased biliary recovery of AG occurred despite a Pb-induced increase in the fraction of the acetaminophen dose converted to AG. Similarly, biliary recovery of AS was reduced further than expected based on Pb-associated decreases in the fraction of the acetaminophen dose converted to AS. These observations suggest that the hepatobiliary disposition of AG and AS was altered at multiple sites due to 1) direct interactions with Pb (or a Pb metabolite) and/or 2) metabolic induction by Pb. Renal ligation shifted the metabolic pathway toward sulfation, with a subsequent increase in biliary recovery of AS. However, renal ligation did not alter the percentage of the dose excreted as AG in bile despite a marked elevation in AG serum concentrations. Furthermore, biliary excretion rate vs. time profiles of AG and AS in renal-ligated rats exhibited a terminal half-life exceeding that of acetaminophen in serum. These data provide evidence that diffusional barriers between blood and hepatocytes influence the hepatic disposition and routes of elimination of polar metabolites such as AG and AS.

Acetaminophen↗