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1.
Anesthesiology ; 103(6): 1183-8, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16306730

ABSTRACT

BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats. METHODS: Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology. RESULTS: Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity. CONCLUSIONS: Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.


Subject(s)
Anesthetics, Inhalation/pharmacology , Ethers/metabolism , Ethers/toxicity , Hydrocarbons, Fluorinated/metabolism , Hydrocarbons, Fluorinated/toxicity , Kidney/drug effects , Methyl Ethers/pharmacology , Animals , Biotransformation , Ethers/urine , Hydrocarbons, Fluorinated/urine , Kidney/pathology , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Kidney Function Tests , Male , Rats , Rats, Inbred F344 , Sevoflurane , Sulfoxides/metabolism
2.
Clin Pharmacokinet ; 44(7): 731-51, 2005.
Article in English | MEDLINE | ID: mdl-15966756

ABSTRACT

OBJECTIVE: Levo-alpha-acetylmethadol (LAAM, levacetylmethadol) is a long-acting opioid agonist used for the prevention of opioid withdrawal. LAAM undergoes sequential N-demethylation to norLAAM and dinorLAAM, which are more potent and longer-acting than LAAM. Hepatic and intestinal microsomal N-demethylation in vitro is catalysed mainly by cytochrome P450 (CYP) 3A4; however, the role of CYP3A in LAAM disposition in humans in vivo is unknown. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) LAAM metabolism and bioactivation and, thus, clinical effects. It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect. METHODS: Healthy volunteers (n = 13) completed the three-way, randomised, balanced crossover study. Subjects received oral LAAM (0.25 mg/kg) after CYP3A induction (rifampicin [rifampin]), inhibition (troleandomycin) or nothing (controls). Plasma and urine LAAM, norLAAM and dinorLAAM were determined by electrospray high-performance liquid chromatography/mass spectrometry (HPLC/MS). Dark-adapted pupil diameter change from baseline (miosis) was the LAAM effect measure. Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model. RESULTS: Compared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC(infinity) 199 +/- 91 [control] versus 11.3 +/- 4.0 [rifampicin] and 731 +/- 229 ng . h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC(96)) [norLAAM + dinorLAAM] (859 +/- 241 versus 107 +/- 48 and 1185 +/- 179 ng . h/mL; p < 0.05) and clinical effects (mean miosis AUC(96) 128 +/- 40 versus 22.5 +/- 14.9 and 178 +/- 81 mm . h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations. CONCLUSION: CYP3A mediates human LAAM N-demethylation and bioactivation to norLAAM and dinorLAAM in vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validate in vitro drug metabolism studies.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Methadyl Acetate/pharmacokinetics , Administration, Oral , Adult , Algorithms , Analgesics, Opioid/adverse effects , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/pharmacology , Area Under Curve , Cross-Over Studies , Cytochrome P-450 CYP3A/physiology , Cytochrome P-450 CYP3A Inhibitors , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Female , Humans , Male , Methadyl Acetate/analogs & derivatives , Methadyl Acetate/blood , Methadyl Acetate/urine , Miosis/chemically induced , Models, Biological , Receptors, Opioid, mu/agonists , Reproducibility of Results , Rifampin/administration & dosage , Rifampin/pharmacology , Troleandomycin/administration & dosage , Troleandomycin/pharmacology
3.
Chem Res Toxicol ; 17(9): 1177-89, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15377151

ABSTRACT

The volatile anesthetic sevoflurane is degraded to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) in anesthesia machines. FDVE is nephrotoxic in rats. FDVE undergoes glutathione conjugation, subsequent conversion to cysteine and mercapturic acid conjugates, and cysteine conjugate metabolism by renal beta-lyase, which is a bioactivation pathway mediating nephrotoxicity in rats. Recent in vitro studies revealed cytochrome P4503A-catalyzed formation of novel sulfoxide metabolites of FDVE cysteine-S and mercapturic acid conjugates in rat liver and kidney microsomes. FDVE-mercapturic acid sulfoxides were more toxic than other FDVE conjugates to renal proximal tubular cells in culture. Nevertheless, the occurrence and toxicological significance of FDVE sulfoxides formation in vivo remain unknown. This investigation determined, in rats in vivo, the existence, role of P4503A, and nephrotoxic consequence of FDVE conjugates sulfoxidation. Rats were pretreated with dexamethasone, phenobarbital, troleandomycin, or nothing (controls) before FDVE, and then, nephrotoxicity, FDVE-mercapturate sulfoxide urinary excretion, and FDVE-mercapturate sulfoxidation by liver microsomes were assessed. The formation of FDVE-mercapturic acid sulfoxide metabolites in vivo and their urinary excretion were unambiguously established by mass spectrometry. Dexamethasone and phenobarbital increased, and troleandomycin decreased (i) liver microsomal FDVE-mercapturic acid sulfoxidation in vitro, (ii) FDVE-mercapturic acid sulfoxide urinary excretion in vivo, and (iii) FDVE nephrotoxicity in vivo assessed by renal histology, blood urea nitrogen concentrations, and urine volume and protein excretion. Urine 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, reflecting beta-lyase-dependent FDVE-cysteine S-conjugates metabolism, was minimally affected by the pretreatments. These results demonstrate that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in rats in vivo, and this sulfoxidation pathway contributes to nephrotoxicity. FDVE S-conjugates sulfoxidation constitutes a newly discovered mechanism of FDVE bioactivation and toxicification in rats, in addition to beta-lyase-catalyzed metabolism of FDVE-cysteine S-conjugates.


Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Cysteine/metabolism , Ethers/toxicity , Hydrocarbons, Fluorinated/toxicity , Kidney Diseases/chemically induced , Kidney Diseases/enzymology , Oxidoreductases, N-Demethylating/metabolism , Anesthetics, Inhalation/metabolism , Anesthetics, Inhalation/toxicity , Animals , Aryl Hydrocarbon Hydroxylases/drug effects , Cytochrome P-450 CYP3A , Dexamethasone/pharmacology , Ethers/metabolism , Hydrocarbons, Fluorinated/metabolism , Lyases/metabolism , Male , Methyl Ethers , Oxidoreductases, N-Demethylating/drug effects , Phenobarbital/pharmacology , Propionates/urine , Rats , Rats, Inbred F344 , Sevoflurane , Sulfoxides/metabolism , Sulfoxides/toxicity , Troleandomycin/pharmacology
4.
Article in English | MEDLINE | ID: mdl-15315782

ABSTRACT

A sensitive stereoselective bioanalytical liquid chromatographic assay with mass spectrometric detection (LC-MS) was developed and validated for the on-line extraction and quantification of R- and S-methadone and the primary metabolite R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) from human plasma. Deproteinized plasma was injected directly onto a small C8 column, washed and then back-flushed using a column switching valve and a second pump onto an alpha1-acid glycoprotein analytical column, and enantioselective separation achieved using a mobile phase gradient of methanol and ammonium formate. Analytes were validated over a range of 0.1-25 ng/ml R- and S-EDDP and 0.1-100ng/ml R- and S-methadone, respectively. Unweighted standard curves were linear over this concentration range (regression coefficients > 0.999). Quality control samples were evaluated at 1, 5, 12.5 ng/ml R- and S-EDDP and 1, 10, 50 ng/ml R- and S-methadone. Intra- and inter-day accuracy was >95%, and intra- and inter-day coefficients of variation were less than 10% for all analytes and concentrations. This assay represents the only method currently available which combines on-line extraction and achieves chiral separation of both methadone and EDDP from plasma, and offers improvements in sensitivity over existing methods.


Subject(s)
Chromatography, Liquid/methods , Mass Spectrometry/methods , Methadone/blood , Pyrrolidines/blood , Automation , Humans , Sensitivity and Specificity
5.
Clin Pharmacol Ther ; 74(6): 543-54, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14663457

ABSTRACT

INTRODUCTION: There is considerable and unexplained individual variability in the morphine dose-effect relationship. The efflux pump P-glycoprotein regulates brain access and intestinal absorption of numerous drugs. Morphine is a P-glycoprotein substrate in vitro, and P-glycoprotein affects morphine brain access and pharmacodynamics in animals. However, the role of P-glycoprotein in human morphine disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous morphine are greater after inhibition of intestinal and brain P-glycoprotein, with the P-glycoprotein inhibitor quinidine used as an in vivo probe. METHODS: Two randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in normal healthy volunteers after institutional review board-approved informed consent was obtained. In the first protocol, pupil diameter was evaluated after intravenous morphine administration (0.15 mg/kg), 1 hour after oral quinidine or placebo. In the second protocol, plasma morphine and glucuronide metabolite concentrations and pupil diameters were evaluated after oral morphine administration (30 mg), dosed 1 hour after oral quinidine (600 mg) or placebo. RESULTS: Quinidine had no effect on intravenous morphine effects (time to maximum miosis, maximum effect, or area under the curve [AUC] of miosis versus time). Quinidine increased the oral morphine maximum plasma concentration (31.8 +/- 14.9 ng/mL versus 16.9 +/- 7.4 ng/mL, P <.05) and AUC (65.1 +/- 21.5 versus 40.8 ng. h. mL(-1) +/- 14 ng. h. mL(-1), P <.05) but had no effect on elimination rate. Plasma morphine glucuronide concentrations were unchanged; however, the morphine glucuronide/morphine ratios were diminished by quinidine. Differences in oral morphine miosis (AUC, 16.8 +/- 9.3 mm. h versus 10.8 +/- 6.5 mm. h; P <.05) were commensurate with changes in plasma morphine concentration, and concentration-effect relationships were unchanged. Quinidine altered subjective self-assessments of oral but not intravenous morphine effects. DISCUSSION: Quinidine increased the absorption and plasma concentrations of oral morphine, suggesting that intestinal P-glycoprotein affected the absorption, bioavailability, and, hence, clinical effects of oral morphine. However, quinidine had no effect on morphine concentration-effect relationships, suggesting that if quinidine is an effective inhibitor of brain P-glycoprotein then P-glycoprotein did not appear to have a significant effect on brain access of morphine.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Adrenergic alpha-Antagonists/pharmacology , Analgesics, Opioid/pharmacology , Morphine/pharmacology , Quinidine/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/pharmacology , Administration, Oral , Adrenergic alpha-Antagonists/pharmacokinetics , Adult , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/pharmacokinetics , Area Under Curve , Cross-Over Studies , Double-Blind Method , Drug Interactions , Female , Half-Life , Humans , Injections, Intravenous , Intestinal Absorption/drug effects , Male , Metabolic Clearance Rate , Morphine/administration & dosage , Morphine/pharmacokinetics , Quinidine/pharmacokinetics
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