Disposition Of Acetaminophen Research Articles

Pharmacokinetics of multiple oral doses of acetaminophen in equine neonates.

To determine the pharmacokinetics and clinical safety of acetaminophen after oral administration of 40 mg/kg q 12 hours or 60 mg/kg q 24 hours for 14 days. 12 healthy light-breed neonatal foals. 6 foals received acetaminophen at 40 mg/kg q 12 hours and 6 foals received 60 mg/kg q 24 hours for 14 days. The study dates were January 31 to April 15, 2023. Physical examinations were performed daily. Plasma disposition of acetaminophen was determined after the first, mid-point drug administration. Hematology and biochemistry analysis was performed before the study, day 7, and the last day of drug administration. Plasma acetaminophen concentrations were determined by high-performance liquid chromatography. Plasma pharmacokinetic parameters were estimated using noncompartmental analysis. No statistically significant changes occurred on hematology or biochemistry profiles. Elevations in γ-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were noted in 4 foals at various time points. The maximum plasma concentration (Cmax) occurred within 2 hours for both doses. The 60 mg/kg dose resulted in a larger median Cmax (range) at 28 μg/mL (22-32) than the 40 mg/kg dose at 23 μg/mL (19-27). The median area under the concentration-vs-time curve from 0 to 8 hours (AUC0-8 hour [range]) was 100 h•µg/mL (82-100) at 40 mg/kg and 128 h•µg/mL (120-168) for 60 mg/kg. Trough concentrations decreased over time for both regimens. Foals tolerate oral acetaminophen at 40 mg/kg q 12 hours or 60 mg/kg q 24 hours. Further analgesic and antipyretic studies will help to delineate optimal dosage regimens of acetaminophen to treat foals.

Pharmacokinetics of acetaminophen after a single Oral administration of 20 or 40 mg/kg to 7-9 Day-old foals.

Acetaminophen is utilized in human infants for pain management and fever. Neonatal foals might benefit from administration of acetaminophen but effective and safe dosage regimens for neonatal foals remains to be determined. The objective was to determine the plasma pharmacokinetics of acetaminophen following oral administration of a single dose of 20 mg/kg or 40 mg/kg to neonatal foals. A secondary objective was to evaluate any changes in hematology and biochemistry profiles. Randomized study. Eight clinically healthy 7-9-day old Quarter Horse foals (3 colts and 5 fillies) received a single oral dose of acetaminophen either 20 (n = 4) or 40 (n = 4) mg/kg. Hematology and biochemistry profiles were evaluated before and 7 days after drug administration. Blood samples were collected before and 8 times after acetaminophen administration for 48 h to quantify plasma acetaminophen concentrations. Plasma pharmacokinetic parameters were estimated using non- compartmental analysis. The median peak plasma concentrations (and range) occurred at 1.5 (0.5-2) hours, and 1.0 (1-2) hours for the 20 and 40 mg/kg doses. The maximum plasma concentration (and range) was 12 (7.9-17.4) μg/mL for the 20 mg/kg dose and 14 (11-18) μg/mL for 40 mg/kg dose. The median AUC0-∞ ranged from 46 to 100 and 79 to 160 h*-μg/mL for the 20 and 40 mg/kg dose, respectively. Hematology and biochemistry profiles remained within normal limits. Plasma disposition of acetaminophen after oral administration of 20 and 40 mg/kg to neonates is comparable to adult horses. However, safety and the optimal dosage regimen of acetaminophen for treating pain and or pyrexia in neonates in this age group remains to be determined.

Pharmacokinetics of single dose administration of three increasing doses of acetaminophen per os in 1-3-month-old foals.

Acetaminophen is a common analgesic and antipyretic drug used in human medicine and might be an alternative to nonsteroidal anti-inflammatory drugs for treating pain and pyrexia in foals. The pharmacokinetics and safety of differing doses of acetaminophen have not been investigated in foals. To determine the plasma pharmacokinetics and any changes in haematology and biochemistry profiles following oral administration of single doses of acetaminophen at 10, 20, and 40 mg/kg to foals. Randomised cross-over pharmacokinetic study. Six Quarter Horse (two colts and four fillies) foals received 10, 20, and 40 mg/kg acetaminophen orally once. Haematology and biochemistry profiles were performed before and 7 days after each drug administration. Blood samples were collected over 64 h after drug administration and were used to quantify plasma acetaminophen concentrations by liquid chromatography. Pharmacokinetic parameters were determined using compartmental analysis. Median (range) acetaminophen plasma concentrations were 4.4 (1.8-5.1), 6.3 (2.6-12.6), and 14 (7.3-18)μg/ml for the 10, 20, and 40 mg/kg doses, respectively. Median acetaminophen area under the concentration versus time curve (AUC)0-∞ ranged from 25 (11-32), 41 (22-74), and 105 (82-142)h × μg/ml for the 10, 20, and 40 mg/kg doses, respectively. Dose-normalised maximal concentrations and AUC0-∞ values were similar across dose concentrations (p > 0.05). Median terminal half-life for all doses was 2.7-2.8h. Haematology and biochemistry profiles were normal except for blood urea nitrogen and alkaline phosphatase concentrations. Foals were growing throughout the study, starting at 1month and ending at 3months. Deposition of drugs changes with age. The sample size was small and only single doses were evaluated. No liver biopsies were performed. Plasma disposition of acetaminophen after a single oral dose of 10, 20, and 40 mg/kg to 1-3-month-old foals varies greatly with the dose. The analgesic and antipyretic effect in foals is unknown.

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

Manipulation of the Gut Microbiome Alters Acetaminophen Biodisposition in Mice

The gut microbiota is a vast and diverse microbial community that has co-evolved with its host to perform a variety of essential functions involved in the utilization of nutrients and the processing of xenobiotics. Shifts in the composition of gut microbiota can disturb the balance of organisms which can influence the biodisposition of orally administered drugs. To determine how changes in the gut microbiome can alter drug disposition, the pharmacokinetics (PK), and biodistribution of acetaminophen were assessed in C57Bl/6 mice after treatment with the antibiotics ciprofloxacin, amoxicillin, or a cocktail of ampicillin/neomycin. Altered PK, and excretion profiles of acetaminophen were observed in antibiotic exposed animals. Plasma Cmax was significantly decreased in antibiotic treated animals suggesting decreased bioavailability. Urinary metabolite profiles revealed decreases in acetaminophen-sulfate metabolite levels in both the amoxicillin and ampicillin/neomycin treated animals. The ratio between urinary and fecal excretion was also altered in antibiotic treated animals. Analysis of gut microbe composition revealed that changes in microbe content in antibiotic treated animals was associated with changes in acetaminophen biodisposition. These results suggest that exposure to amoxicillin or ampicillin/neomycin can alter the biodisposition of acetaminophen and that these alterations could be due to changes in gut microbiome composition.

Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis

Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.

Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice

BackgroundType-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites.ResultsTransporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice.ConclusionA severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels.

Age-Related Pseudocapillarization of the Liver Sinusoidal Endothelium Impairs the Hepatic Clearance of Acetaminophen in Rats

We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer (14)C-acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 ± 0.04, old; 0.59 ± 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k(1) (0.34 ± 0.10 s(-1), old; 0.61 ± 0.38 s(-1), young; p < .05) and the permeability-surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 ± 0.006 mL/s/g, old; 0.048 ± 0.014 mL/s/g, young; p < .005). There was no difference in k(3), the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver.

Expression of Drug Pump Protein MRP2 in Lipopolysaccharide-Treated Rats and its Impact on the Disposition of Acetaminophen.

The drug pump protein MRP2 is a membrane drug efflux transporter widely distributed in normal and tumor tissues. Its role is thought to be crucial for the disposition of many drugs and their substrates in different tissues. In this study, we aimed to examine the effects of systematic inflammation induced by lipopolysaccharide (LPS) on the expression and function of this transporter in rats. Jugular cannulated rats were injected intraperitoneally with LPS. Control rats received equal volume of sterile saline buffer. Rat liver MRP2 expression was analyzed at the level of mRNA through reverse transcription polymerase chain reaction. At various time points following drug administration (15 to 360 min), 250 μL blood samples were obtained from the cannula. The plasma was separated by centrifugation and stored at -20°C until HPLC analysis. Administration of LPS resulted in a slight but not significant increase in MRP2 mRNA levels 24 h after the treatment. In HPLC analysis, a rapid decrease in plasma concentrations of the MRP2 substrate (APAP) was observed at the initial time points. At later time points, the slope of the substrate concentration reached a plateau and paralleled to those of controls. It was postulated that due to the presence of the possible compensatory transport mechanisms in liver and non-hepatic tissues, changes performed to the pump activity were not completely in parallel to the expression of the drug efflux pump.

Disposition of Acetaminophen at 4, 6, and 8 g/day for 3 Days in Healthy Young Adults

The objective of this study was to determine the disposition and tolerability of 1, 1.5, and 2 g acetaminophen every 6 h for 3 days. Group I healthy adults received acetaminophen (4 then 6 g/day) or placebo; Group II received acetaminophen (4 then 8 g/day) or placebo. Acetaminophen and metabolites were measured in plasma and urine. Hepatic aminotransferases were measured daily. At steady state, acetaminophen concentrations were surprisingly lower than predicted from single-dose data, although sulfate formation clearance (fCL) was lower as expected, indicating cofactor depletion with possible sulfotransferase saturation. In contrast, glucuronide fCL was unexpectedly higher, strongly suggesting glucuronosyltransferase induction. This is the first evidence that acetaminophen induces its own glucuronidation. No dose-dependent differences were detected in fCL of thiol metabolites formed via cytochrome P4502E1. Hepatic aminotransferases stayed within reference ranges, and the incidence and frequency of adverse events were similar for acetaminophen and placebo. Although dose-dependence of acetaminophen disposition was reported previously, this study shows a novel finding of time-dependent disposition during repeated dosing. Unexpected increases in glucuronide fCL more than offset decreases in sulfate fCL, thus increasing acetaminophen clearance overall. Thiol metabolite fCL remained constant up to 8 g/day. These findings have important implications in short-term (3 day) tolerability of supratherapeutic acetaminophen doses in healthy adults.

Aminotransferase activities in healthy subjects receiving three-day dosing of 4, 6, or 8 grams per day of acetaminophen

Introduction. This multiple-dose pharmacokinetic study has a randomized, double-blind, placebo-controlled, parallel-group design with three dosing regimens. Healthy subjects received repeated doses of acetaminophen (4 then 6 g/d or 4 then 8 g/d) or placebo. Methods. The disposition of acetaminophen and its metabolites and the tolerability of increased acetaminophen doses over 3 days of continuous consumption were characterized. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities measured throughout the study were consistent across the acetaminophen 4, 6, and 8 g/d dose levels and with placebo. Results. Serum aminotransferase activities did not exceed the upper limit of the reference range (ULRR), except for one subject with an AST of 43 U/L (ULRR, 42 U/L), which was not considered clinically significant. All doses were generally well tolerated. Conclusions. In a multiple-dose pharmacokinetics study of 4, 6, and 8 g/d of acetaminophen for 3 days, multiple aminotransferase determinations demonstrated no clinically important elevations at 1, 1.5, or 2 times the maximum recommended acetaminophen dose.

Altered Disposition of Acetaminophen in Mice With a Disruption of the Mrp3 Gene * #

MRP3 is an ABC transporter localized in the basolateral membrane of epithelial cells such as hepatocytes and enterocytes. In this study, the role of Mrp3 in drug disposition was investigated. Because Mrp3 preferentially transports glucuronide conjugates, we investigated the in vivo disposition of acetaminophen (APAP) and its metabolites. Mrp3+/+ and Mrp3-/- knockout mice received APAP (150 mg/kg), and bile was collected. Basolateral and canalicular excretion of APAP was also assessed in the isolated perfused liver. In separate studies, mice received 400 mg APAP/kg for assessment of hepatotoxicity. No differences were found in the biliary excretion of APAP, APAP-sulfate, and APAP-glutathione between Mrp3+/+ and Mrp3-/- mice. However, 20-fold higher accumulation of APAP-glucuronide (APAP-GLUC) was found in the liver of Mrp3-/- mice. Concomitantly, plasma APAP-GLUC content in Mrp3-/- mice was less than 10% of that in Mrp3+/+ mice. In addition, APAP-GLUC excretion in bile of Mrp3-/- mice was tenfold higher than in Mrp3+/+ mice. In the isolated perfused liver, we also found a strong decrease of APAP-GLUC secretion into the perfusate of Mrp3-/- livers. Plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histopathology showed that Mrp3-/- mice are more resistant to APAP hepatotoxicity than Mrp3+/+ mice, which is most likely a result of the faster repletion of hepatic GSH. In conclusion, basolateral excretion of APAP-GLUC in mice is nearly completely dependent on the function of Mrp3. In its absence, sufficient hepatic accumulation occurs to redirect some of the APAP-GLUC to bile. This altered disposition in Mrp3-/- mice is associated with reduced hepatotoxicity.

Effect of Taurine on Biliary Excretion and Metabolism of Acetaminophen in Male Hamsters

The effect of taurine intake on the biliary disposition and toxicity of acetaminophen (APAP) was examined in male Golden-Syrian hamsters. Animals were provided with taurine (5 mM) in drinking water for 1 week followed by APAP treatment (250 mg/kg, i.p.). Biliary excretion and plasma concentrations of APAP and its major metabolites were determined for up to 360 min. Taurine increased the bile flow, whereas the concentration of APAP or the metabolites in bile was not altered significantly. Accordingly the total biliary excretion of APAP and the metabolites was increased in hamsters fed taurine. Taurine increased the plasma concentrations of APAP-glutathione (GSH) and APAP-mercapturate, but the APAP-glucuronide or APAP-sulfate concentration was not changed. The area under the curve of the plasma APAP concentration was reduced significantly, suggesting that the elimination of APAP was enhanced by taurine intake. However, the hepatotoxicity resulting from a dose of APAP (450 mg/kg, i.p.) was not altered by taurine intake as determined by the elevation of serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities. The results suggest that taurine administration could affect the disposition of APAP by enhancing its metabolism through the GSH-dependent pathway and also by increasing the biliary excretion of this drug and its metabolites. The pharmacological significance of this finding remains to be examined.

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice.

Drug treatment poses a therapeutic challenge in cystic fibrosis (CF) because the disposition of a number of drugs is altered in CF. Enhanced clearance of acetaminophen (APAP) and indocyanine green (ICG) have previously been reported in CF patients. The objective of the current study was to investigate if the CF-knockout mouse model (cftr(m1UNC)) shows altered pharmacokinetics similar to those seen in CF patients using the 2 model compounds APAP and ICG. Clearance (CL/F) of APAP and renal (CLR) and formation (CLf) clearance of acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were determined in CF-knockout mice following administration of APAP (50 mg/kg, intraperitoneal). CLR of AS was 19.5 and 12.9 (mL/min per kg) and CLf of AS was 10.4 and 6.7 mL/min per kg for homozygous and heterozygous males, respectively, which was significantly different between groups. CLR of AG was 6.3 and 4.8 mL/min per kg and CLf of AG was 9.6 and 8.9 mL/min per kg for homozygous and heterozygous males, respectively, although not reaching statistical significance. No significant differences were noted in either ClR or CLf of AG and AS in female CF mice. Plasma concentrations of ICG (10 mg/kg, intravenous) were determined over 0 to 15 minutes. Homozygous females showed a higher apparent volume of distribution (96 mL/kg) relative to heterozygous females (72 mL/kg). Similar to CF patients, a trend toward a lower Cmax was noted in homozygous male and female mice. However, contrary to human data, no significant differences in CL of ICG were noted. These results suggest that the CF-knockout mice have potential as a model for studying altered drug disposition in CF patients.

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice

1. The effects of clofibrate (CFB) and indocyanine green (ICG) on the biliary excretion of acetaminophen (APAP) and its metabolites were investigated. 2. Male CD-1 mice were pretreated with 500 mg CFB/kg, i.p. for 10 days. Controls received corn oil vehicle only. After overnight fasting, common bile duct-cannulated mice were challenged with a non-toxic dose of APAP (1 mmol/kg, i.v.). 3. CFB pretreatment did not affect bile flow rate, nor did it affect the cumulative biliaryexcretion of APAP and its conjugated metabolites. 4. Additional CFB or corn oil pretreated mice were given 30 μmol indocyanine green(ICG)/kg, i.v., immediately before APAP dosing. ICG is a non-metabolizable organic anion that is completely excreted into the bile through a canalicular transport process for organic anions. 5. ICG significantly decreased the bile flow rate and biliary concentration of APAPglutathione, APAP-glucuronide and APAP-mercapturate within the first hour after dosing without affecting the biliary concentration of APAP.6. The results indicate thatCFB pretreatment does not affect the total amount of APAP and its metabolites excreted in bile. They also suggest that the biliary excretion of several conjugated metabolites of APAP share the same excretory pathway with the organic anion ICG.

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.

Pharmacokinetic monitoring in subcutaneous tissue using in vivo capillary ultrafiltration probes.

Capillary ultrafiltration probes were utilized for in vivo sampling of therapeutic drugs in awake rats. Capillary ultrafiltration probes implanted into subcutaneous tissue were able to follow the disposition of acetaminophen and theophylline. Ultrafiltration probes provided samples at a rate of 2-3 microL/min. Ultrafiltrates were analyzed by liquid chromatography with either UV or electrochemical detection. Simultaneous ultrafiltration and microdialysis probes and multiple ultrafiltration probes were used in individual animals to validate the technique. The pharmacokinetics of two well-established drugs, acetaminophen and theophylline, were monitored in awake, freely moving rats to demonstrate the viability of the technique. The half-life for acetaminophen was determined to be 20.9 +/- 1.0 min (n = 6) for a 2 mg/kg dosing. The half-life of elimination for theophylline was determined to be 3.0 +/- 0.1 hr (n = 4) for a 4 mg/kg dose. The capillary ultrafiltration probes exhibited a constant flow rate of 2.4 +/- 0.1 microL/min and removed 50 nL/min/mm of fluid from the extracellular space. Capillary ultrafiltration sampling is shown to be an excellent tool for in vivo monitoring of drug disposition and a suitable method for determining pharmacokinetic parameters in awake animals.

Disposition of drugs in cystic fibrosis. III. Acetaminophen

The disposition of acetaminophen after oral administration was investigated in adults with cystic fibrosis (n = 5) and in age-matched healthy control subjects (n = 5). The total plasma clearance of acetaminophen was found to be greater (p less than 0.025) in subjects with cystic fibrosis (0.362 +/- 0.081 L/hr/kg) than in control subjects (0.247 +/- 0.022 L/hr/kg). This difference in clearance was found to be primarily attributable to a greater metabolic clearance of acetaminophen to acetaminophen sulfate (0.080 +/- 0.023 L/hr/kg for subjects with cystic fibrosis and 0.045 +/- 0.008 L/hr/kg for control subjects; p less than 0.05) and to a greater metabolic clearance of acetaminophen to acetaminophen glucuronide (0.189 +/- 0.051 L/hr/kg for subjects with cystic fibrosis and 0.114 +/- 0.017 L/hr/kg for control subjects; p less than 0.05) in persons with cystic fibrosis. Of the mechanisms that may be responsible for these differences, the most likely is enhanced activity (in subjects with cystic fibrosis) of the transferases that mediate the metabolism of acetaminophen to acetaminophen sulfate and acetaminophen glucuronide, respectively.