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ABSTRACT: Multiple studies suggest that phenytoin concentrations increase with CBZ co-medication. This study evaluated the hypothesis that CBZ and/or its major metabolite (CBZE) inhibit CYP2C19-mediated phenytoin metabolism using human liver microsomes and cDNA-expressed CYP2C19. Oxcarbazepine (OXC), and its 10-monohydroxy metabolite (MHD) were also evaluated. CBZ and MHD inhibited CYP2C19-mediated phenytoin metabolism at therapeutic concentrations. Thus, administration of CBZ and OXC with CYP2C19 substrates with narrow therapeutic ranges should be done cautiously.
Epilepsy Research 01/2003; 52(2):79-83. · 2.29 Impact Factor
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ABSTRACT: Acute tubular cell injury is accompanied by plasma membrane phospholipid breakdown. Although cholesterol is a dominant membrane lipid which interdigitates with, and impacts, phospholipid homeostasis, its fate during the induction and recovery phases of acute renal failure (ARF) has remained ill defined. The present study was performed to ascertain whether altered cholesterol expression is a hallmark of evolving tubular damage. Using gas chromatographic analysis, free cholesterol (FC) and esterified cholesterol (CE) were quantified in: 1) isolated mouse proximal tubule segments (PTS) after 30 minutes of hypoxic or oxidant (ferrous ammonium sulfate) injury; 2) cultured proximal tubule (HK-2) cells after 4 or 18 hours of either ATP depletion/Ca(2+) ionophore- or ferrous ammonium sulfate-mediated injury; and 3) in renal cortex 18 hours after induction of glycerol-induced myoglobinuric ARF, a time corresponding to the so-called "acquired cytoresistance" state (ie, resistance to further renal damage). Hypoxic and oxidant injury each induced approximately 33% decrements in CE (but not FC) levels in PTS, corresponding with lethal cell injury ( approximately 50 to 60% LDH release). When comparable CE declines were induced in normal PTS by exogenous cholesterol esterase treatment, proportionate lethal cell injury resulted. During models of slowly evolving HK-2 cell injury, progressive CE increments occurred: these were first noted at 4 hours, and reached approximately 600% by 18 hours. In vivo myoglobinuric ARF produced comparable renal cortical CE (and to a lesser extent FC) increments. Renal CE accumulation strikingly correlated with the severity of ARF (eg, blood urea nitrogen versus CE; r, 0.84). Mevastatin blocked cholesterol accumulation in injured HK-2 cells, indicating de novo synthesis was responsible. Acute tubule injury first lowers, then raises, tubule cholesterol content. Based on previous observations that cholesterol has cytoprotectant properties, the present findings have potential relevance for both the induction and maintenance phases of ARF.
American Journal Of Pathology 10/2000; 157(3):1007-16. · 4.89 Impact Factor
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ABSTRACT: CYP2E1, 1A2, and 3A4 have all been implicated in the formation of N-acetyl-p-benzoquinone imine (NAPQI), the reactive intermediate of acetaminophen (INN, paracetamol), in studies in human liver microsomes and complementary deoxyribonucleic acid-expressed enzymes. However, recent pharmacokinetic evidence in humans has shown that the involvement of CYP1A2 is negligible in vivo. The purpose of this study was to evaluate the respective roles of CYP2E1 and 3A4 in vivo.
The involvement of CYP2E1 was assessed through pretreatment of adult human volunteers with disulfiram to inhibit the enzyme and the role of CYP3A4 through its induction in a second cohort of adults with rifampin (INN, rifampicin). Each of the respective studies was an open-label, balanced-randomized crossover design. Blood samples were obtained serially for 12 hours and urine was collected for 24 hours after acetaminophen administration. Acetaminophen was assayed in plasma, and acetaminophen and metabolites were assayed in urine.
The recovery of the thiol metabolites formed by conjugation of NAPQI with glutathione was decreased by 69%, and the formation clearance of NAPQI was decreased by 74% (both P < .01) by pretreatment with disulfiram. Rifampin pretreatment had no effect on the formation of NAPQI or the recovery of thiol metabolites formed by conjugation of NAPQI with glutathione.
CYP2E1 accounts for the formation of NAPQI in intact humans; the contribution of other isozymes of cytochrome P450 appears to be negligible. Under some conditions, disulfiram may be useful in diminishing the formation of NAPQI after acetaminophen overdose.
Clinical Pharmacology & Therapeutics 04/2000; 67(3):275-82. · 6.04 Impact Factor
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ABSTRACT: An assay method for the quantification of cyclophosphamide (CY) and five metabolites from human plasma is presented. The procedure is adapted to the chemical properties of the compounds of interest: non-polar compounds are extracted into methylene chloride, concentrated and analyzed by GC-NPD after derivatization, and the remaining aqueous fraction is deproteinated with acetonitrile-methanol prior to separation via reversed-phase HPLC and detection using atmospheric pressure ionization (API)-MS. Standard curves are linear over the required range and reproducible over five months. Plasma concentration-time profiles of CY and metabolites from a patient receiving CY by intravenous infusion (60 mg/kg, once a day for two days) are presented.
Journal of chromatography. B, Biomedical sciences and applications 10/1999; 732(2):287-98.
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ABSTRACT: In a previous study, we observed that the elimination clearance of 4-hydroxycyclophosphamide (HCY) in patients receiving cyclophosphamide (CY) 60 mg/kg/day by 1-h i.v. infusion for 2 consecutive days decreased from day 1 to day 2 due to an apparent decrease in human aldehyde dehydrogenase 1 (ALDH1) activity. Here, the mechanism for the decrease in ALDH1 activity after CY administration was investigated. In human liver cytosol incubations, HCY inhibited ALDH activity mainly through its degradation product acrolein, whereas carboxyethylphosphoramide mustard inhibited ALDH activity only at supraclinical concentrations. Other CY metabolites evaluated, phosphoramide mustard and chloroacetaldehyde, did not inhibit ALDH. The inhibition of ALDH1 activity by acrolein in incubations with human erythrocyte ALDH1 was competitive with a Ki of 0.646 microM. The inhibition was independent of preincubation time and reversible by dialysis. The percentage of inhibition of ALDH1 activity in vivo by acrolein in patients receiving CY was calculated based on the in vitro Ki of acrolein, the in vitro Km of HCY, and the in vivo peak blood concentrations of HCY and acrolein. The calculations indicated that the activity of ALDH1 was inhibited by 85, 88, and 91% on days 1, 2, and 3 (24 h after the dose on day 2) of CY administration, respectively. The increase in ALDH1 inhibition with time is consistent with the decrease in HCY elimination clearance and the increase in HCY area under the plasma concentration time curve with time.
Drug Metabolism and Disposition 02/1999; 27(1):133-7. · 3.73 Impact Factor
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ABSTRACT: E-Delta 2-valproic acid (E-Delta 2-VPA), a major active metabolite of VPA, has been proposed as an alternative to VPA because it is less hepatotoxic and is nonteratogenic. In rodents, VPA and E-Delta 2-VPA have a brain tissue/free plasma concentration ratio less than unity, which suggests rapid removal of the alkanoate anticonvulsants from the central nervous system. This study in rabbits employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique to investigate the steady-state kinetics of E-Delta 2-VPA transport at the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell membrane. Probenecid (PBD) was coadministered to probe the mediation of transport by organic anion transporter(s). Rabbits in the control group (N = 6) received an iv infusion of E-Delta 2-VPA to achieve a steady-state plasma concentration of 50 to 60 microg/ml. Blood and cisternal outflow of mock CSF perfusate were continuously sampled. Midway through the experiment, the VC perfusate was switched to one containing [3H]E-Delta 2-VPA. At 225 min, the rabbits were sacrificed, and each brain was removed and dissected into ten regions. Rabbits in the PBD group (N = 9) received an iv infusion and VC perfusion as in the control group as well as concomitant iv infusion of the inhibitor. The mean steady-state VC extraction ratio for [3H]E-Delta 2-VPA did not differ between the control and PBD groups (63.7 +/- 8.3% vs. 60. 6 +/- 9.6%), indicating the lack of a significant PBD-sensitive transport at the choroidal epithelium. Coadministration of PBD elevated brain concentration of cold E-Delta 2-VPA in the absence of a significant change in total or free steady-state plasma concentration. Mean E-Delta 2-VPA brain tissue/free plasma concentration ratios in the various brain regions were 3.5- to 5.2-fold higher in PBD-treated animals than in the controls. Significant increases (3.0- to 4.5-fold) in the mean brain tissue/cisternal perfusate concentration ratios were also observed. Compartmental modeling of the steady-state distribution data suggested that clearance of E-Delta 2-VPA from the brain parenchyma is governed jointly by efflux transporters at the neural cell membrane and brain capillary endothelium. Moreover, PBD-induced elevation of E-Delta 2-VPA tissue concentrations is attributed primarily to inhibition of E-Delta 2-VPA efflux transport at the neural cell membrane, resulting in both intracellular trapping and greater tissue retention of E-Delta 2-VPA.
Drug Metabolism and Disposition 01/1998; 25(12):1337-46. · 3.73 Impact Factor
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ABSTRACT: We have investigated the formation of 4-hydroxycyclophosphamide (HCY) and deschloroethylcyclophosphamide (DCCY) from cyclophosphamide (CY) in human liver microsomes. For HCY, the estimated values (mean +/- SD; n = 3) of Km1 and Km2 were 0.095 +/- 0.072 and 5.09 +/- 4.30 mM, and the estimated values of Vmax1 and Vmax2 were 0.138 +/- 0.070 and 1.55 +/- 0.50 nmol/min/mg protein. For DCCY, Km1 and Km2 were 0.046 +/- 0.017 and 8.58 +/- 5.84 mM, and Vmax1 and Vmax2 were 0.006 +/- 0.003 and 0.274 +/- 0.214 nmol/min/mg protein. At CY concentrations of 0.1, 0.7, and 5 mM, HCY respectively accounted for 95.7 +/- 1.3, 95.1 +/- 2.4, and 90.7 +/- 2.7% of the total products of CY (HCY + DCCY; n = 6). In a separate experiment, 98.7 +/- 11.9% (n = 3) of CY loss could be accounted for by the formation of HCY at 0.1 mM CY. On the basis of cytochrome P450 (CYP) isoform-specific chemical inhibitor and cDNA-expressed human P450 isozyme studies, CYP2C9 and CYP3A4/5 seemed to be the major P450 isoforms responsible for HCY formation at low (0.1 mM) and high (0.7 and 5 mM) concentrations of CY, respectively. Although orphenadrine inhibition was observed in human liver microsomes (which has been taken to indicate CYP2B6 catalysis), orphenadrine inhibited cDNA-expressed CYP3A4 formation of HCY to the same extent observed in human liver microsomes, and the addition of orphenadrine to incubations containing sulfaphenazole (a specific inhibitor of CYP2C9) or troleandomycin (a specific CYP3A inhibitor) did not increase inhibition beyond that observed with sulfaphenazole or troleandomycin alone. Similar studies indicated that CYP3A4/5 was the major P450 isoform responsible for DCCY formation at high (0.7 and 5 mM) concentrations of CY. The P450 isoform responsible for DCCY formation at 0.1 mM CY could not be identified due to its very low formation rate.
Cancer Research 11/1997; 57(19):4229-35. · 7.86 Impact Factor
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ABSTRACT: The disposition of carbamazepine (CBZ) was investigated in the SWV mouse. A 14C-CBZ dose was administered to CBZ pretreated mice, and the distribution of radiolabeled material was determined. Twenty-four hours after the 14C-CBZ dose, 92.5% of the dose was accounted for in urine (56%), in the visera and carcass (22%), in feces (11%), and expired as 14CO2 (2%). CBZ metabolites present in hydrolyzed urine were also identified using a combination of spectroscopic techniques. CBZ, CBZ-10,11-epoxide (CBZE), 2- and 3-hydroxy-CBZ, methylsulfonyl-CBZ, and glucuronides of CBZ and CBZE accounted for 64% of total urinary radioactivity (0-24 hr) in CBZ pretreated mice. Minor metabolites of CBZ included novel cysteine and N-acetylcysteine conjugates of CBZ, as well as a methylsulfonyl conjugate of CBZE not previously reported. The urinary excretion of these thioether conjugates was increased in CBZ/phenobarbital pretreated mice and decreased in CBZ/stiripentol pretreated mice in comparison with CBZ-only treated mice. Preliminary studies of the effects of phenobarbital and stiripentol on the urinary abundance of these metabolites are consistent with the modulation of teratogenicity in the SWV mouse by the same pretreatments. These data suggest the formation of thioether metabolites of CBZ may be related to CBZ teratogenicity in the SWV mouse.
Drug Metabolism and Disposition 09/1997; 25(8):953-62. · 3.73 Impact Factor
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ABSTRACT: The mechanism of carbamazepine (CBZ)-related teratogenicity was investigated in the SWV mouse by contrasting the effects of CBZ-10, 11-epoxide (CBZE) and oxcarbazepine (OXC) treatments. Dietary CBZE administration was initiated 2 weeks before mating and continued through day 18 of gestation. OXC was administered to pregnant dams by gavage on day 6 of gestation and continued through day 18 of gestation. Maternal plasma concentrations of CBZE ranged from 1.4 to 17.7 micrograms/ml and OXC ranged from 6.1 to 15.9 micrograms/ml. In comparison, clinical plasma concentrations of CBZE ranged from 1 to 2 micrograms/ml and OXC plasma concentrations were 1 microgram/ml or less. The incidence of malformation were 14%, 27% and 26% after daily CBZE doses of 300, 600 and 1000 mg/kg, respectively, compared with a 6% incidence in no-drug control mice, P < .05. The incidence of malformation was 8% after exposure at the highest tolerable dose of OXC (1100 mg/kg/day), compared with a 5% incidence in no-drug controls, P > .05. Phenobarbital cotreatment (45 mg/kg/day) with OXC (1100 mg/kg/day) did not lead to changes in the incidence of malformation when compared with OXC (1100 mg/kg/day) dosed alone. These data are consistent with a teratogenic CBZ metabolite, possibly CBZE, or with oxidation of CBZE or CBZ at positions on the aromatic ring leading to the formation of reactive intermediates such as arene oxides or quinones.
Journal of Pharmacology and Experimental Therapeutics 12/1996; 279(3):1237-42. · 3.83 Impact Factor
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ABSTRACT: The metabolism of lisofylline and pentoxifylline were examined in cytosol and microsomes prepared from four human livers to determine whether pentoxifylline is likely to serve as an efficient prodrug for the more active inhibitor of phosphatidic acid-dependent cell signaling, lisofylline, and to determine the extent to which lisofylline is converted to pentoxifylline, a hemorheologic agent used for the treatment of intermittent claudication. Pentoxifylline is exclusively reduced to the optical antipode of lisofylline (S M-1) in human liver cytosol, whereas the reduction in microsomes is 85% stereoselective in favor of S M-1 formation. The intrinsic clearance (Vmax/KM) of S M-1 formation in cytosol was 4 times that in microsomes. In human liver microsomes, S M-1 is exclusively converted to pentoxifylline, whereas approximately 45% of lisofylline oxidation is accounted for by the formation of pentoxifylline and the balance by aliphatic diols. It is concluded that pentoxifylline is an inefficient prodrug for delivery of lisofylline and that formation of pentoxifylline accounts for approximately 40% of the microsomal metabolites formed from lisofylline at substrate concentrations likely to be encountered in human therapeutic applications.
Drug Metabolism and Disposition 12/1996; 24(11):1174-9. · 3.73 Impact Factor
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ABSTRACT: The character of reactive metabolites formed from carbamazepine (CBZ) was sought in incubations of [14C]CBZ in hepatic microsomes prepared from adult female mice of a strain (SWV/Fnn) susceptible to CBZ-induced teratogenicity. The formation of radio-labeled protein adducts was used as an index of reactive metabolite exposure. A dependence on cytochrome P450 was shown by a requirement for NADPH and inhibition by carbon monoxide, 1-aminobenzotriazole, piperonyl butoxide, and stiripentol. The addition of ascorbic acid, caffeic acid, N-acetylcysteine, and glutathione decreased the rate of binding of the radiolabel from [14C]CBZ to microsomal protein by more than 50%. The addition of glutathione transferases diminished protein adduct formation beyond that seen with glutathione alone. Evidence for the formation of an arene oxide was sought through the use of inhibitors of epoxide hydrolases, including cyclohexene oxide, chalcone oxides (with the addition of cytosol as appropriate), and by the addition of recombinant human soluble and microsomal epoxide hydrolases and recombinant rat microsomal epoxide hydrolase. The microsomal epoxide hydrolases decreased the velocity of 14C-labeled protein adduct formation by approximately 23%, whereas inhibitors had no effect, most likely because of the low native activity of microsomal epoxide hydrolase in mice. Both DT-diaphorase and catechol-O-methyltransferase diminished 14C-labeled protein adduct formation by 54% and 45%, respectively. The data suggest that the major reactive metabolites formed from CBZ by adult female SWV/Fnn liver microsomes are quinones and arene oxides.
Drug Metabolism and Disposition 06/1996; 24(5):509-14. · 3.73 Impact Factor
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ABSTRACT: The pharmacokinetics of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (HCY) were studied in 14 patients being prepared for bone marrow transplantation with either busulfan (BU)/CY (n = 7) or CY/total-body irradiation (TBI) (n = 7) to determine whether exposure to CY and its proximate toxic metabolite HCY is modulated by other agents used in the preparative regimen.
HCY was assayed by a new method that stabilized the metabolite at bedside. In BU/CY patients (who also received phenytoin), CY clearance was 112% greater (P = .0014), half-life 54% less (P = .0027), peak HCY concentration in plasma/CY dose 113% greater (P = .0006), and the ratio of area under the plasma concentration-time curves (AUCs) of HCY to CY 166% greater (P = .0116) than in CY/TBI patients. The ratio of the AUC of HCY/CY dose was 48% greater in BU/CY patients than in CY/TBI patients when one CY/TBI patient with an apparent impaired ability to eliminate HCY was excluded from analysis. In CY/TBI patients, there was an inverse correlation between the AUC of HCY and that of CY (R2 = .740, P = .028). Also, the ratio of the AUC of HCY/CY dose was correlated with the average concentration of BU at steady-state (Css, Bu) (R2 = .646, P = 0.29). Variability in CY and HCY pharmacokinetics among the 14 patients overall was pronounced, with the highest variability (15-fold) observed in the ratio of the AUC of HCY to that of CY.
Prior administration of BU and/or phenytoin significantly alters exposure to CY and HCY. Interpatient variability in HCY exposure at a given CY dose is substantial.
Journal of Clinical Oncology 06/1996; 14(5):1484-94. · 18.37 Impact Factor
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ABSTRACT: The widely used analgesic/antipyretic agent 4'-hydroxyacetanilide (acetaminophen, APAP) is oxidized by cytochromes P450 to a potent cytotoxin, N-acetyl-p-benzoquinone imine (NAPQI), and a nontoxic catechol, 3',4'-dihydroxyacetanilide (3-hydroxyacetaminophen, 3-OH-APAP). There are marked differences in the ratios of these two products formed from different isoforms of cytochrome P450. For example, the ratio of NAPQI to 3-OH-APAP formed by rat liver CYP1A1 was found to be approximately 3:1, whereas the ratio of the same two products formed by rat liver CYP2B1 was approximately 1:5. Investigations of the binding of APAP to CYP1A1 and CYP2B1 were carried out to assess the possibility that different preferred orientations of APAP in the active sites of these isoforms may, in part, by responsible for their different product selectivities. Although the spectral dissociation constants (Ks congruent to 0.85 mM) and UV-vis binding spectra (type I; absorption minimum congruent to 420 nm, absorption maximum congruent to 390 nm) were similar for interactions of APAP with the two P450 isoforms, NMR longitudinal relaxation times (T1) of APAP nuclei were significantly different. Two isotopically substituted analogs of APAP, [2,3',5'-13C3]-4'-hydroxyacetanilide and 4'-hydroxyacet-[15N]-anilide, were synthesized, and their binding to purified CYP1A1 and CYP2B1 was examined by NMR spectroscopy. Paramagnetic relaxation times (T1p) for each of the labeled nuclei were calculated from the T1 values obtained before (ferric) and after (ferrous-CO) treatment with Na2S2O4 and CO. The Solomon-Bloembergen equation was then used to calculate distances of the isotopically labeled nuclei from the heme iron of each P450 isoform. The results were that the amide nitrogen approaches relatively close to the heme iron in CYP1A1 (3.64 +/- 0.51 A) whereas it is significantly further away (> 4.5 A) in CYP2B1. In contrast, the aryl carbon atoms ortho to the phenolic group of APAP approach closer to the heme iron of CYP2B1 (3.19 +/- 0.12 A) than to the heme iron of CPY1A1 (3.66 +/- 0.30 A). The results are consistent with the hypothesis that CYP1A1 produces NAPQI preferentially because of closer proximity of the heme iron to the amide nitrogen, whereas CYP2B1 produces 3-OH-APAP preferentially because of closer proximity of the heme iron to the phenolic oxygen in this isoform.
Journal of Medicinal Chemistry 03/1994; 37(6):860-7. · 5.25 Impact Factor
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ABSTRACT: 1. The effect of isoniazid given daily for 7 days on paracetamol (acetaminophen) kinetics and metabolism was studied in 10 healthy volunteers. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. 2. On day 7, isoniazid markedly inhibited the formation clearance of the glutathione and catechol metabolites by 69.7% and 62.2%, respectively. Total paracetamol clearance was lowered by 15.2%. There was no effect of isoniazid on the non-oxidative pathways of paracetamol elimination. 3. Two days after isoniazid was discontinued, paracetamol metabolism had returned to pre-isoniazid values.
British Journal of Clinical Pharmacology 03/1991; 31(2):139-42. · 2.96 Impact Factor
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ABSTRACT: The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3-methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene-induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.
Journal of Pharmacology and Experimental Therapeutics 02/1990; 252(1):112-6. · 3.83 Impact Factor
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ABSTRACT: The effect of cimetidine administration on the disposition of acetaminophen was evaluated in seven men and six women. One gram of acetaminophen was administered to each volunteer after an overnight fast on two occasions in a balanced crossover design with and without cimetidine, 300 mg every 6 hours beginning 50 hours before acetaminophen administration and continuing for 22 hours after. N-Acetylcysteine was administered on both occasions when acetaminophen was ingested to protect against glutathione depletion. Blood samples were collected serially for 12 hours after acetaminophen administration, and total urine volume was collected for 24 hours. Fractional clearances of acetaminophen through renal and metabolic routes (sulfation, glucuronidation, 3-hydroxylation, and glutathione conjugate formation) were not altered by cimetidine administration. Studies in microsomes prepared from two human organ donors indicated that cimetidine inhibited acetaminophen reactive metabolite formation noncompetitively, with Ki values of 0.35 mmol/L and 0.32 mmol/L for the respective livers, which is 5 to 10 times the putative cimetidine concentration required for therapeutic effect.
Clinical Pharmacology & Therapeutics 12/1989; 46(5):591-7. · 6.04 Impact Factor
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ABSTRACT: A thermospray high-performance liquid chromatography-mass spectrometry method for the separation and quantification of tracer concentrations of isotopically labelled carbamazepine epoxide ([15N, 13C]CBZE) in the presence of steady-state levels of the anticonvulsant carbamazepine (CBZ) and its epoxide metabolite (CBZE) has been developed. The technique does not require derivatization, demonstrates little or no thermal degradation of the analytes, provides increased specificity not available from conventional high-performance liquid chromatography, and has a detection limit of 500 pg for CBZE on-column. The method, incorporating d4-CBZ and d4-CBZE as internal standards, allows precise and accurate determination of the analytes with good reproducibility and stability.
Journal of Chromatography 08/1989; 474(1):223-30. · 4.53 Impact Factor
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ABSTRACT: The time course of excretion of acetaminophen and its metabolites in urine was determined in eight healthy adults (seven men and one woman) who ingested 1 gm of the drug and collected timed urine samples for 24 hours. The mean time of peak excretion rate was 1.3 to 3.7 hours for acetaminophen, its glucuronide, sulfate, cysteine, mercapturate, and methoxy metabolites but 13.5 hours for methylthioacetaminophen. The mean half-life of acetaminophen was 3.1 hours and the mean half-life of the metabolites other than methylthioacetaminophen ranged from 4.1 to 5.7 hours. The half-life of methylthiometabolite could not be determined because of its very late peak time. In a second study the effect of dose on the clearance of acetaminophen was determined in nine healthy adult subjects (eight men and one woman) who received doses of 0.5 and 3 gm acetaminophen on separate occasions, separated by 4 to 10 days. The renal clearance of acetaminophen and the formation clearances of the sulfate, glutathione, and catechol metabolites were lower (by 38%, 41%, 35%, and 46%, respectively) at the higher dose. The renal clearance of acetaminophen sulfate and glucuronide conjugates were not different between doses. In a third study (10 men), 10 gm N-acetylcysteine was found to increase the formation clearance of the sulfate conjugate by 27% and that of the glutathione conjugate by 10%. The data suggest that the hepatic supply of reduced glutathione and 3'-phosphoadenosine 5'-phosphosulfate begins to be depleted over the range of 0.5 to 3 gm acetaminophen and that the depletion is overcome by the administration of N-acetylcysteine.
Clinical Pharmacology & Therapeutics 05/1987; 41(4):413-8. · 6.04 Impact Factor
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ABSTRACT: To evaluate the possibility of estimating ethanol plasma level from a record of voluntary intake, the effects of food, mild stress, and distributed dosing on the fraction of ethanol absorbed and the relative exposure to circulating blood ethanol were determined in four adult male pigtailed macaques (Macaca nemestrina). The animals received 0.6 g/kg ethanol IV and orally after an 18-hour fast, after a small meal, and under mild stress; distributed dosing was evaluated for the oral route only. The concentration-time profile for the oral/fasting condition was very similar to that following an IV dose. The dose was completely absorbed and peak plasma level occurred about 30 min after ingestion. Peak plasma concentration was reduced by 42% following a small meal, 29% following mild stress, and 18% following distribution of the dose over 60 min. The time to peak concentration was more than doubled by distributed dosing. Relative exposure was reduced by 18 to 27% by all conditions of oral administration except feeding, which caused a 52% reduction. The fraction of ethanol absorbed was influenced only by feeding, which caused a reduction of 20%. The magnitude of changes in concentration-time profile produced by such factors precludes accurate estimation of blood levels from records of voluntary intake. Furthermore, the effects of social factors on voluntary ethanol consumption may be mediated by centrally controlled changes in gastrointestinal function that alter the rate and extent of absorption of the drug.
Pharmacology Biochemistry and Behavior 04/1986; 24(3):491-6. · 2.53 Impact Factor
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ABSTRACT: The pharmacokinetics of IV ethanol (0.6 g/kg) were examined in 11 male colony-bred pigtailed macaques (Macaca nemestrina) aged 3 to 13 years. The animals were either chaired during blood sampling (4 hr) or connected to a tether system that allowed injections and blood sampling while the animal moved freely about its cage. In all instances, ethanol pharmacokinetics could be described by a single Michaelis-Menten function; inclusion of a parallel first-order rate constant to account for non-alcohol dehydrogenase elimination of ethanol did not improve the fit. Volume of distribution was 0.802 +/- 0.054 L/kg (mean +/- SD), Km (the apparent in vivo Michaelis constant) was 0.063 +/- 0.022 micrograms/ml, and Vmax was 0.199 +/- 0.039 g/kg/hr. The pharmacokinetic parameter values of chaired and tethered monkeys did not differ. Three of the tethered monkeys received 3 g/kg of ethanol daily for two weeks by IV infusion (subchronic administration). Ethanol pharmacokinetics, determined on five occasions before and five occasions after subchronic ethanol administration, showed that the treatment did not alter the volume of distribution or Km in any of the three monkeys. The value of Vmax increased approximately 23% in one of the three monkeys that received subchronic ethanol; this increase may have been due to a single, inadvertent administration of a 4.5-g/kg dose over a 20-min period. Vmax did not change in the other two monkeys.
Pharmacology Biochemistry and Behavior 04/1986; 24(3):485-9. · 2.53 Impact Factor
