Does AMP-activated protein kinase couple hypoxic inhibition of oxidative phosphorylation to carotid body excitation?
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AMP-Activated Protein Kinases↗
Biomedical subjects
A M Evans
Publications and source records attributed to A M Evans.
Prediction of drug absorption based on immobilized artificial membrane (IAM) chromatography separation and calculated molecular descriptors.
The aim of this study was to evaluate the usefulness of IAM chromatography in building a model that would allow prediction of drug absorption in humans. The human intestinal absorption values (%HIA) for 52 drugs with low to high intestinal absorption were collected from the literature. The retention (capacity factor, k') of each drug was measured by reverse-phase HPLC using an IAM.PC.DD2 column (prepared with phosphatidylcholine analogs, 12 microM, 300A, 15 cm x 4.6 mm) with an eluent of acetonitrile-0.1M phosphate buffer at pH 5.4. In addition, 76 molecular descriptors and solubility parameters for each drug were calculated using ChemSW from the 3D-molecular structures. Stepwise regression was employed to develop a regression equation that would correlate %HIA with molecular descriptors and k'. Human intestinal absorption was reciprocally correlated to the negative value of the capacity factor (-1/k') (R=0.64). The correlation was further improved with the addition of molecular descriptors representing molecular size and shape (molecular width, length and depth) solubility (solubility parameter, HLB, hydrophilic surface area) and polarity (dipole, polar surface area) (R=0.83). Experimentally measured IAM chromatography retention values and calculated molecular descriptors and solubility parameters can be used to predict intestinal absorption of drugs in humans. Developed QSAR can be used as a screening method in the designing of drugs with appropriate IA and for the selection of drug candidates in the early stage of drug discovery process.
Chromatography, High Pressure Liquid↗
The quantification of paracetamol, paracetamol glucuronide and paracetamol sulphate in plasma and urine using a single high-performance liquid chromatography assay.
A range of analytical methods exist for the determination of paracetamol in biological fluids. However, to understand the fate of paracetamol and the effect of other drugs on its disposition in vivo, the major metabolites require quantification in urine and plasma. A method to simultaneously quantify paracetamol, paracetamol glucuronide (PG) and paracetamol sulphate (PS) in plasma and urine with superior sensitivity is therefore desired, especially if the volume of plasma available is low. A simple isocratic reverse phase high-performance liquid chromatography (HPLC) assay with spectrophotometric detection has been developed. The method, requiring only 100 microl of plasma and 50 microl of urine, utilizes a reversed-phase C18 column, a wavelength of 254 nm for detection and a mobile phase composed of potassium dihydrogen orthophosphate (0.1 M)-isopropanol-tetrahydrofuran (THF) (100:1.5:0.1, v/v/v) adjusted to pH 3.7 with phosphoric acid. The method is sensitive and linear in plasma within a concentration range from 0.4 to 200 microM for paracetamol, PG and PS. For PG and PS in urine, the method is sensitive and linear within a concentration range from 100 to 20,000 microM. Over these ranges, accuracy and precision were less than 12%. The assay has been used to measure concentrations of paracetamol and the two metabolites in plasma collected by finger-prick sampling and of the metabolites in urine from healthy volunteers administered a single oral dose of 1000 mg of paracetamol.
Acetaminophen↗
Effect of ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S- and inactive R-enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were divided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 micrograms mL-1, n = 5) over three 30-min periods. Treatment groups were perfused with methotrexate (25 micrograms m-1) for the first period, followed by a second period of methotrexate (25 micrograms mL-1) plus R- (n = 5), S- (n = 5) or RS-ketoprofen (n = 4) at 25 micrograms mL-1, and a third period of methotrexate (25 micrograms mL-1) plus R-, S- or RS-ketoprofen (50 micrograms mL-1). Perfusate and urine were collected over 10-min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by dividing the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R-, S- and RS-ketoprofen at 50 micrograms mL-1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.
Animals↗
Cyclic ADP-ribose is the primary trigger for hypoxic pulmonary vasoconstriction in the rat lung in situ.
Hypoxic pulmonary vasoconstriction (HPV) is unique to pulmonary arteries, and it aids ventilation/perfusion matching. However, in diseases such as emphysema, HPV can promote hypoxic pulmonary hypertension. We recently showed that hypoxia constricts pulmonary arteries in part by increasing cyclic ADP-ribose (cADPR) accumulation in the smooth muscle and, thereby, Ca(2+) release by ryanodine receptors. We now report on the role of cADPR in HPV in isolated rat pulmonary arteries and in the rat lung in situ. In isolated pulmonary arteries, the membrane-permeant cADPR antagonist, 8-bromo-cADPR, blocked sustained HPV by blocking Ca(2+) release from smooth muscle ryanodine-sensitive stores in the sarcoplasmic reticulum. Most importantly, we showed that 8-bromo-cADPR blocks HPV induced by alveolar hypoxia in the ventilated rat lung in situ. Inhibition of HPV was achieved without affecting (1) constriction by membrane depolarization and voltage-gated Ca(2+) influx, (2) the release (by hypoxia) of an endothelium-derived vasoconstrictor, or (3) endothelium-dependent vasoconstriction. Our findings suggest that HPV is both triggered and maintained by cADPR in the rat lung in situ.
Adenosine Diphosphate Ribose↗
Comparative pharmacology of S(+)-ibuprofen and (RS)-ibuprofen.
Racemic ibuprofen, which contains equal quantities of R(-)-ibuprofen and S(+)-ibuprofen, has been used as an anti-inflammatory and analgesic agent for over 30 years. Although the S(+)-enantiomer is capable of inhibiting cyclooxygenase (COX) at clinically relevant concentrations, R(-)-ibuprofen is not a COX inhibitor. The two enantiomers of ibuprofen are therefore different in terms of their pharmacological properties and may be regarded as two different 'drugs'. They also differ in terms of their metabolic profiles. For example, R(-)-ibuprofen becomes involved in pathways of lipid metabolism and is incorporated into triglycerides along with endogenous fatty acids. S(+)-Ibuprofen does not appear to become involved in these unusual metabolic reactions, which is why S(+)-ibuprofen is regarded as being metabolically 'cleaner' than racemic ibuprofen. When racemic ibuprofen is given to humans, a substantial fraction of the dose of R(-)-ibuprofen (50%-60%) undergoes 'metabolic inversion' to yield S(+)-ibuprofen. On this basis, it has been argued that to obtain clinical effects that are comparable to those of a given dose of racemic ibuprofen, the dose of S(+)-ibuprofen would need to be about 75% of the dose of the racemate. However, this 'pharmacokinetic' rationale does not take into account the fact that inversion is not instantaneous, that there is variability in the extent of inversion between individuals, and that the kinetics of inversion may differ depending on the dosing situations. For example, the extent of inversion appears to be reduced when the racemate is given to patients experiencing acute pain. Recent studies have demonstrated that the clinical benefits of racemic ibuprofen can be derived from the administration of the single S(+)-enantiomer at a dose that is half that of the racemate. For example, 200 mg of S(+)-ibuprofen has been found to be superior or at least equivalent to 400 mg of the racemate in the relief of dental pain. Possible explanations for this higher than expected efficacy of S(+)-ibuprofen are considered.
Anti-Inflammatory Agents, Non-Steroidal↗
Selection of high-level oxacillin resistance in heteroresistant Staphylococcus aureus by fluoroquinolone exposure.
To study the effect of fluoroquinolone exposure on the expression of mec(A)-encoded oxacillin resistance, population analysis profiling was performed on four strains of fluoroquinolone-susceptible, mec(A)-positive, heteroresistant Staphylococcus aureus. Growth in the presence of 0.5 x MIC of a fluoroquinolone resulted in >10-fold increase in the proportion of the population that grew on agar containing oxacillin 128 mg/L. Ciprofloxacin exhibited a greater effect than moxifloxacin, levofloxacin and gatifloxacin (average 3400-, 220-, 170- and 49-fold increase in oxacillin-resistant colonies versus the control, respectively). The increase was directly proportional to the fluoroquinolone concentration and could be detected as early as 8 h after exposure to the fluoroquinolone. At 8 h, the absolute number of colonies that grew on oxacillin 128 mg/L was similar whether or not the isolate was exposed to the fluoroquinolone, but the total cfu on non-selective media decreased. The resultant oxacillin-resistant colonies also showed a 1.5- to 3-fold increase in fluoroquinolone MIC. No oxacillin resistance was observed on two similarly treated fluoroquinolone-susceptible, mec(A)-negative strains. It appears that fluoroquinolones influence oxacillin resistance by selective inhibition or killing of the more susceptible subpopulations in heteroresistant S. aureus. The surviving populations are more resistant to both oxacillin and fluoroquinolone. The mechanisms of resistance to the two agents may be unrelated but tend to be associated. This could explain in part the observed increases in fluoroquinolone-resistant MRSA.
Anti-Infective Agents↗
Hypoxic release of calcium from the sarcoplasmic reticulum of pulmonary artery smooth muscle.
The hypoxic constriction of isolated pulmonary vessels is composed of an initial transient phase (phase 1) followed by a slowly developing increase in tone (phase 2). We investigated the roles of the endothelium and of intracellular Ca2+ stores in both preconstricted and unpreconstricted intrapulmonary rabbit arteries when challenged with hypoxia (PO2 16-21 Torr). Removing the endothelium did not affect phase 1, but phase 2 appeared as a steady plateau. Removing extracellular Ca2+ had essentially the same effect as removing the endothelium. Depletion of sarcoplasmic reticulum Ca2+ stores with caffeine and ryanodine abolished the hypoxic response. Omitting preconstriction reduced the amplitude of the hypoxic response but did not qualitatively affect any of the above responses. We conclude that hypoxia releases intracellular Ca2+ from ryanodine-sensitive stores by a mechanism intrinsic to pulmonary vascular smooth muscle without the need for Ca2+ influx across the plasmalemma or an endothelial factor. Our results also suggest that extracellular Ca2+ is required for the release of an endothelium-derived vasoconstrictor.
Animals↗
Scope of practice issues in forensic nursing.
1. There is significant role variation, across the Western world, in relation to how forensic nurses practice. 2. The authors conducted a pilot survey of forensic nurses in Australia, New Zealand, the United States, and the United Kingdom to examine forensic nursing practice, role definition, and role boundaries. 3. Issues arising from the data include the visibility of forensic nurses, the client group, forensic-specific education, and role development.
Australia↗
Adp-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor. a primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction.
Hypoxic pulmonary vasoconstriction is unique to pulmonary arteries and serves to match lung perfusion to ventilation. However, in disease states this process can promote hypoxic pulmonary hypertension. Hypoxic pulmonary vasoconstriction is associated with increased NADH levels in pulmonary artery smooth muscle and with intracellular Ca(2+) release from ryanodine-sensitive stores. Because cyclic ADP-ribose (cADPR) regulates ryanodine receptors and is synthesized from beta-NAD(+), we investigated the regulation by beta-NADH of cADPR synthesis and metabolism and the role of cADPR in hypoxic pulmonary vasoconstriction. Significantly higher rates of cADPR synthesis occurred in smooth muscle homogenates of pulmonary arteries, compared with homogenates of systemic arteries. When the beta-NAD(+):beta-NADH ratio was reduced, the net amount of cADPR accumulated increased. This was due, at least in part, to the inhibition of cADPR hydrolase by beta-NADH. Furthermore, hypoxia induced a 10-fold increase in cADPR levels in pulmonary artery smooth muscle, and a membrane-permeant cADPR antagonist, 8-bromo-cADPR, abolished hypoxic pulmonary vasoconstriction in pulmonary artery rings. We propose that the cellular redox state may be coupled via an increase in beta-NADH levels to enhanced cADPR synthesis, activation of ryanodine receptors, and sarcoplasmic reticulum Ca(2+) release. This redox-sensing pathway may offer new therapeutic targets for hypoxic pulmonary hypertension.
ADP-ribosyl Cyclase↗
Hepatic disposition of fexofenadine: influence of the transport inhibitors erythromycin and dibromosulphothalein.
PURPOSE: To examine the disposition of fexofenadine in the isolated perfused rat liver and the influence of erythromycin and dibromosulphthalein (DBSP) on the hepatic uptake and biliary excretion of fexofenadine. METHODS: Livers from four groups of rats were perfused in a recirculatory manner with fexofenadine HCl added as a bolus (125, 250, 500, or 1000 microg) to perfusate. Livers from another three groups of rats were perfused with 250 microg of fexofenadine HCl. With one group as control, erythromycin (4.0 microg/ml) or DBSP (136 microg/ml) was added to the perfusate of the other groups. In all experiments, perfusate and bile were collected for 60 min; in addition, livers from the second experiment were retained for assay. Fexofenadine was determined in perfusate, bile, and homogenized liver by HPLC. RESULTS: The area under the curve (AUC) of fexofenadine was linearly related to concentration. It was unchanged from control (12,800 +/- 200 ng x h/ml) by erythromycin (14,400 +/- 2000 ng x h/ml), but was increased 95% by DBSP (25,000 +/- 2600 ng x h/ml, P <0.001). The ratios of the concentrations of fexofenadine in liver/perfusate were decreased significantly by DBSP; those for bile/liver were increased by erythromycin. CONCLUSIONS: Erythromycin reduced the canalicular transport of fexofenadine into bile, whereas DBSP reduced uptake across the sinusoidal membrane.
Animals↗
Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat.
We have examined the effects of Y-27632, a specific inhibitor of Rho-activated kinases (ROCK I and ROCK II) upon sustained hypoxic pulmonary vasoconstriction (HPV) in both rat isolated small intrapulmonary arteries (IPA) and perfused rat lungs in situ. Y-27632 (100 nM - 3 microM) was found to cause a concentration-dependent inhibition of acute sustained HPV in rat IPA. Application of Y-27632 (10-600 nM) in perfused rat lungs caused no change in basal perfusion pressure, but was found to inhibit HPV in a concentration-dependent manner, resulting in complete ablation of the pressor response to hypoxia at a concentration of 600 nM. Furthermore, addition of Y-27632 at any point during hypoxia caused a reversal of HPV in perfused rat lungs. These results suggest that activation of Rho-associated kinase may be a pivotal step in the generation of sustained HPV.
Amides↗
Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsorption.
AIMS: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. METHODS: This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. RESULTS: All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. CONCLUSIONS: Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.
Absorption↗
Pharmacokinetics of L-carnitine in patients with end-stage renal disease undergoing long-term hemodialysis.
OBJECTIVE: L-Carnitine is an endogenous molecule involved in fatty acid metabolism. Secondary carnitine deficiency may develop in patients with end-stage renal disease undergoing long-term hemodialysis because of dialytic loss. In these patients L-carnitine can be administered to restore plasma and tissue levels. The objective of this study was to evaluate the pharmacokinetics of intravenous L-carnitine in patients undergoing long-term hemodialysis. METHODS: Twelve patients undergoing three dialysis sessions/week received L-carnitine intravenously (20 mg x kg(-1)) at the end of each dialysis session for 9 weeks. Plasma samples were analyzed for L-carnitine, acetyl-L-carnitine, and total carnitine by HPLC. RESULTS: Under baseline conditions, the mean +/- SD predialysis plasma concentration of L-carnitine was 19.5 +/- 5.6 micromol/L, decreasing to 5.6 +/- 1.9 micromol/L at the end of the dialysis session. These concentrations were substantially lower than endogenous levels in healthy human beings. Under baseline conditions the extraction ratios of L-carnitine and acetyl-L-carnitine by the dialyser were 0.74 +/- 0.07 and 0.71 +/- 0.11, respectively. During repeated dosing, there was accumulation of L-carnitine in plasma, and after 9 weeks of dosing, the predialysis and postdialysis plasma levels were 191 +/- 54.1 and 41.8 +/- 13.0 micromol/L, respectively. The predialysis and postdialysis plasma levels of L-carnitine decreased once dosing was ceased but had not returned to pretreatment levels after 6 weeks. CONCLUSION: The study demonstrated that removal of L-carnitine by hemodialysis is extremely efficient and that patients undergoing hemodialysis had plasma concentrations that were substantially lower than normal, particularly during dialysis. During repeated administration of L-carnitine, the predialysis and postdialysis concentrations of the compound increased steadily, reaching an apparent steady state after about 8 weeks. It is proposed that this accumulation arose from the distribution of L-carnitine into a deep tissue pool that includes skeletal muscle.
Acetylcarnitine↗
Influence of dietary components on the gastrointestinal metabolism and transport of drugs.
There is widespread recognition that the ingestion of a meal is associated with a number of physiologic changes (gastric pH, gastric emptying, hepatic blood flow, etc.) that can significantly alter the rate and extent of drug absorption. It is also well recognized that the components of food can alter drug absorption through alterations in drug solubility. The nutritional status of a patient can also contribute to variability in the pharmacokinetics of certain drugs. The more recent finding that grapefruit juice can increase the bioavailability of certain drugs, by reducing presystemic intestinal metabolism, has led to renewed interest in the area of 'food-drug interactions.' Particular interest has focused on the effects of the grapefruit flavonoid, naringin, and the furanocoumarin, 6',7'-dihydroxybergamottin, on the activity of intestinal CYP3A4. The possibility that grapefruit juice might affect drug absorption via an interaction with intestinal P-glycoprotein (P-gp) is also being explored. The growing use of herbal extracts and phytopharmaceuticals raises a new challenge-will the use of these products cause changes in the pharmacokinetics of 'conventional' drugs? As a case in point, consider the phytoestrogenic isoflavones, which are being promoted for a number of health benefits. Isoflavones such as genistein and daidzein can inhibit oxidative and conjugative metabolism in vitro and interact with transporters such as P-gp and the canalicular multispecific organic anion transporter. Given that P-gp and canalicular multispecific organic anion transporter are involved in the intestinal absorption and biliary excretion of a wide range of drugs and metabolites, it is reasonable to suspect that isoflavones may alter drug disposition in humans. However, this possibility has not been explored.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Vancomycin and oxacillin synergy for methicillin-resistant staphylococci.
An increase in oxacillin activity was observed against methicillin-resistant coagulase-negative staphylococci (MRCNS) and methicillin-resistant Staphylococcus aureus (MRSA) in the presence of a sub-MIC of vancomycin. Vancomycin and oxacillin were synergistic against 14 of 21 strains of MRCNS and MRSA. A pattern of enhanced killing was also supported by time-kill studies. These results suggest that combinations of sub-MICs of vancomycin and oxacillin may have therapeutic benefits against methicillin-resistant staphylococci.
Drug Synergism↗
Hepatic disposition of electrophilic acyl glucuronide conjugates.
Acyl glucuronides are a unique class of electrophilic metabolites, capable of non-enzymatic reactions including acylation and/or glycation of endogenous macromolecules, hydrolysis to reform the parent aglycone, and intra-molecular rearrangement. Three human UDP-glucuronosyltransferases (UGTs) catalyzing the hepatic glucuronidation of carboxylic acid drugs have been identified, UGT1A3, UGT1A9 and a UGT2B7 variant. Within the liver, acyl glucuronides also undergo enzymatic hydrolysis by beta-glucuronidase and esterases which, like the UGTs, are located in the endoplasmic reticulum. In addition, the liver also transports acyl glucuronides between the sinusoidal circulation and bile. Due to their polarity, membrane transport of acyl glucuronides is carrier-mediated, resulting in the establishment of significant concentration gradients between sinusoidal circulation, hepatocyte and bile, in the order of 1:50:5,000 in these compartments, respectively. As a result of exposure to high acyl glucuronide concentrations, the liver is a major target of protein adduct formation. Dipeptidylpeptidase IV, UGTs and tubulin have been identified as intra-hepatic targets of adduct formation by acyl glucuronides. Adduct formation results in altered protein activity and potentially contributes to hepatotoxicity. Hepatic protein adducts are also immunogenic and may cause immune mediated cytotoxicity. Both intra- and extra-hepatic exposure to acyl glucuronides depends not only on the efficiency of glucuronidation and hydrolysis by the liver, but also on the efficiency of the hepatic membrane transport systems. Thus, changes in membrane transporter activities, as may occur due to saturation or drug-drug interactions, can significantly affect acyl glucuronide disposition, adduct formation and the disposition of parent aglycone, thereby affecting clinical efficacy and toxicity of acyl glucuronide forming drugs.
Animals↗
Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide.
Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-beta-D-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 microM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 microM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean +/- S. D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 +/- 1.4 ml/min, 94.1 +/- 17.9 ml/min, 0.346 +/- 0.046, and 30.9 +/- 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P <.05) while decreasing its biliary excretion half-life (P <.05), suggesting an interaction between GG and hepatically generated clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.
Acetaminophen↗