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J Uetrecht

Publications and source records attributed to J Uetrecht.

33 records · Page 2Linked to original sources
PubMed1992

Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites.

The intent of this study was to identify pharmacokinetic and pharmacodynamic characteristics for spironolactone (SP) and its metabolites (canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 7 alpha-thiomethylspirolactone) in cirrhotics under steady state conditions. Nine cirrhotics with ascites participated in the study. Serial blood samples were drawn and urine was collected over a 26-hour period. Using a reverse-phase high performance liquid chromatography (HPLC) method, all samples were analyzed for SP, canrenone, 6 beta-hydroxy-7 alpha-thiomethylspirolactone, and 7 alpha-thiomethylspirolactone concentrations. Parent compound and metabolite urinary excretion rates as well as maximal concentrations and time at which these are observed were calculated. The apparent median terminal elimination rate constants (associated half-lives) were 0.0767 h-1 (9.04 hours) for SP, 0.0055 h-1 (126 hours) for 6 beta-hydroxy-7 alpha-thiomethylspirolactone, 0.029 h-1 (23.9 hours) for 7 alpha-thiomethylspirolactone and 0.012 h-1 (57.8 hours) for canrenone. SP metabolism is impaired in cirrhosis; terminal half-lives of SP and metabolites appear to be increased when compared with values reported in the literature for normals. When assuming a linear model, clearance-effect relationship estimates are best correlated with 7 alpha-thiomethylspirolactone and canrenone. Further research is required to identify specific pharmacokinetic and pharmacodynamic parameters for SP and its metabolites in this patient population.

Adult↗
PubMed1991

Metabolism of drugs by activated leukocytes: implications for drug-induced lupus and other drug hypersensitivity reactions.

Despite their importance, little is known about the mechanism of idiosyncratic reactions, many such reactions have characteristics that suggest an immune-mediated mechanism. This is particularly true of drug-induced lupus which is an autoimmune syndrome. Certain functional groups are associated with a high incidence of idiosyncratic reactions, probably reflecting the ease with which they are metabolized to reactive metabolites. Although the liver is the principal organ of drug metabolism, most reactive metabolites generated in the liver would not reach other organs in significant concentrations. Because of the function of leukocytes, especially monocytes, in the induction of an immune response, the generation of reactive metabolites by monocytes would seem likely to lead to an immune-mediated adverse reaction. We have found that drugs that are associated with drug-induced lupus are oxidized to reactive metabolites by the myeloperoxidase system of monocytes. The initial step in drug-induced lupus could be haptenization of a protein on the surface of monocytes by these reactive metabolites. Other types of idiosyncratic drug reactions may involve a similar mechanism and the same drugs that induce lupus are usually associated with a high incidence of other types of idiosyncratic reactions. for example, procainamide, which causes the highest incidence of drug-induced lupus, also causes a relatively high incidence of agranulocytosis. Even some of the therapeutic effects of drugs may involve the production of reactive metabolites by myeloperoxidase or thyroid peroxidase.

Antibody Formation↗
PubMed1990

Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions.

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Agranulocytosis↗
PubMed1989

Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites.

STUDY OBJECTIVE: To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents. DESIGN: In-vitro toxicity assay on lymphocytes. SETTING: Clinics for adverse drug reactions in an adult and pediatric tertiary care center. PATIENTS: Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the clinic for assessment of adverse drug reactions to sulfonamide agents. Thirty-one patients had clinical histories consistent with a diagnosis of hypersensitivity reaction, whereas 45 patients had clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction. INTERVENTIONS: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole. MEASUREMENTS AND MAIN RESULTS: The lymphocytes from patients with a history of hypersensitivity reactions showed markedly increased toxicity across a tenfold-concentration toxicity-concentration curve compared with those from controls and patients with a history of nonhypersensitivity reactions. These differences were highly significant (P less than 0.01). No difference was found between the toxicity shown by the lymphocytes from controls and that shown by the lymphocytes from patients with a history of nonhypersensitivity reactions. CONCLUSIONS: Metabolic differences in the production and detoxification of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to these agents. These results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating these reactions. Sulfonamide hydroxylamines are useful in the diagnosis and study of the pathogenesis of hypersensitivity reactions to sulfonamide agents.

Adult↗
PubMed1989

Mechanism of hypersensitivity reactions: proposed involvement of reactive metabolites generated by activated leukocytes.

Hypersensitivity drug reactions are a major source of serious adverse drug reactions, yet very little is known about their mechanism. Several drugs are oxidized by activated neutrophils and mononuclear cells to reactive metabolites. Jack Uetrecht explains that the pattern of hypersensitivity reactions associated with these drugs - drug-induced lupus, agranulocytosis, and generalized hypersensitivity reactions - fits a mechanism in which leukocyte-generated reactive metabolites initiate the hypersensitivity reaction. Because activation of the leukocyte is necessary for reactive metabolite formation, one risk factor for a drug hypersensitivity reaction may be an infection or other inflammatory condition.

Animals↗
PubMed1988

Metabolism of dapsone to a hydroxylamine by human neutrophils and mononuclear cells.

Dapsone is an effective anti-inflammatory agent in conditions in which inflammation is mediated by neutrophils. Dapsone also has been associated with agranulocytosis. We found that neutrophils, which had been activated by a phorbol ester or opsonized zymosan, oxidized dapsone to its nitroderivative. It appears as if this is due to oxidation of dapsone by myeloperoxidase to the hydroxylamine, followed by nonenzymatic oxidation of the hydroxylamine to the nitroderivative. The hydroxylamine can be isolated if ascorbic acid is added to the incubations. Monocytes also contain myeloperoxidase and activated mononuclear leukocytes also metabolize dapsone to the hydroxylamine. Dapsone also causes a mononucleosis-like syndrome. The reactive hydroxylamine could be responsible for both the pharmacologic and toxic properties of dapsone.

Anti-Inflammatory Agents↗
PubMed1988

Synthesis and in vitro toxicity of hydroxylamine metabolites of sulfonamides.

Among the most serious side effects of sulfonamides are hypersensitivity reactions, the pathogenesis of which has been suggested to be mediated by reactive metabolites. We have previously demonstrated dose-related covalent binding and toxicity of reactive intermediates of sulfonamides generated by a murine hepatic microsomal activating system. We hypothesized that hydroxylamine (H/A) metabolites might be likely candidates for mediating such toxicity; accordingly, we synthesized chemically the H/As of sulfadiazine and sulfamethoxazole. Synthesis was performed using 4-nitrobenzenesulfonyl chloride and either 2-aminopyrimidine or 3-amino-5-methylisoxazole, respectively, as starting materials. The resulting nitro derivatives were reduced to the corresponding H/A with hydrogen in the presence of a poisoned platinum catalyst. After synthesis and purification, toxicity of the H/As to lymphocytes of normal volunteers was evaluated using three cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye conversion, trypan blue dye exclusion and propidium iodide dye exclusion. The H/As of sulfadiazine and sulfamethoxazole displayed dose-related toxicity. 1.6 mM sulfadiazine H/A produced 82% cell death, whereas 400 microM sulfamethoxazole H/A produced 62% cell death; the parent sulfonamides were not toxic to cells. The toxicity of sulfamethoxazole H/A was decreased by coincubation with glutathione or N-acetylcysteine; there was a 47% decrease in toxicity when coincubated with 100 microM glutathione, whereas there was a 55% decrease displayed when coincubation was done with 500 microM N-acetylcysteine. H/A metabolites of the sulfonamides or their nitroso derivatives, normally detoxified by conjugation to glutathione, may be the proximate toxins mediating sulfonamide hypersensitivity.

Cell Survival↗
PubMed1986

The effect of cimetidine on anesthetic metabolism and toxicity.

Because the H2-receptor antagonist cimetidine has been shown to inhibit drug metabolism, the effects of cimetidine on anesthetic metabolism and toxicity were investigated in a rat model. Cimetidine decreased inorganic plasma fluoride production after methoxyflurane administration both in 21% oxygen (P less than 0.001) and in 100% oxygen (P less than 0.001). Phenobarbital produces an increased fluoride formation after methoxyflurane anesthesia, and this fluoride formation is also reduced by cimetidine (P less than 0.005). There was no significant difference between the plasma fluoride levels in rats anesthetized with halothane or enflurane. Although cimetidine inhibited the in vivo defluorination of methoxyflurane, fluoride levels were still within the nephrotoxic range, and cimetidine is not likely to play a role as part of a preanesthetic regimen that would permit the increased clinical use of methoxyflurane. Cimetidine also inhibited the oxidative metabolism of halothane; cimetidine decreased (P less than 0.05) trifluoroacetic acid concentrations after halothane anesthesia in 21% oxygen and in 100% oxygen and decreased (P less than 0.05) bromide concentrations after halothane anesthesia in 100% oxygen. Trifluoroacetic acid levels were less (P less than 0.02) after halothane anesthesia in 14% oxygen as compared with 100% oxygen, indicating a reduction in oxidative metabolism under hypoxic conditions. However, bromide concentrations were maximal after halothane anesthesia in 21% oxygen, and significantly (P less than 0.001) less after halothane anesthesia in 14% and 100% oxygen. Bromide production, therefore, seems to be inhibited by both hypoxia and hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1983

Contrasting effects on halothane hepatotoxicity in the phenobarbital-hypoxia and triiodothyronine model: mechanistic implications.

Factors affecting halothane (H) hepatotoxicity were investigated in two animal models: 1) the phenobarbital-hypoxia model, and 2) the triiodothyronine (T3) model; in the latter we previously have shown that centrilobular necrosis occurs in T3 pretreated rats anesthetized with 1% H, in 21% oxygen for 2 h. Feeding worsens the hepatotoxic effects of H in the T3 model. SGPT levels were higher (P less than 0.001) in T3 pretreated fed animals (641.0 +/- 182.1 U/1) than in T3 pretreated fasted animals (121.9 +/- 30.5 U/1), and histologic grading of hepatic necrosis was more extensive (P less than 0.05) in fed than fasted rats. In contrast, in the phenobarbital-hypoxia model of H hepatotoxicity fasting potentiates the lesion, the severity of histologic grading was worse (P less than 0.001) 24 h after H exposure in fasted than fed rats. Fluoride levels were elevated (P less than 0.001) over control values in the phenobarbital pretreated fasted rats anesthetized with H under hypoxic conditions (15.34 +/- 0.90 microM) but not in T3 pretreated fed rats anesthetized by H in 21% oxygen (2.37 +/- 0.15 microM), indicating that reductive metabolism may not be a prerequisite for toxicity in the T3 model. There was no significant difference in the effect of H and deuterated H on hepatotoxicity in the T3 model. SGPT levels in T3 treated female rats (62.4 +/- 5.1 U/1) were higher (P less than 0.001) than in control female rats (30.5 +/- 1.7 U/1) after H exposure but much less (P less than 0.01) than in male rats (641.0 +/- 182.1 U/1), demonstrating a gender difference for toxicity. These studies show fundamental differences between the two models: 1) hypoxia is required for the phenobarbital-hypoxia model but not for the T3 model; 2) hepatic necrosis correlates with reductive metabolism in the phenobarbital-hypoxia model but not in the T3 model; and 3) nutritional status has important but opposite effects.

Animals↗
PubMed1980

Kinetics of R andS warfarin enantiomers.

A method is reported for simultaneous measurement of the kinetics of R and S warfarin enantiomers. Pure pentadeuterated R and S enantiomers were each combined with unlabeled enatiomers to form "pseudo"-racemic mixtures which were given (0.75 mg/kg) to 5 healthy subjects. Plasma R and S enantiomer levels were measured by gas chromatography--mass spectrometry. Elimination half-lifes (t1/2S) and volumes of distribution (VdS) of the enantiomers were not altered by the presence of the other.

Adult↗
PubMedDate not supplied

Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes.

The chronic use of procainamide is associated with a high incidence of drug-induced lupus and also agranulocytosis. We have previously demonstrated that procainamide is metabolized in the liver to reactive hydroxylamine (PAHA) and nitroso (nitroso-PA) metabolites which covalently bind to protein and are toxic to lymphocytes. We proposed that these metabolites were responsible for the toxicities of procainamide. However, PAHA and nitroso-PA do not appear to escape the liver in significant concentrations. In this paper we describe the metabolism of procainamide to a reactive hydroxylamine by neutrophils and mononuclear leukocytes. Such metabolism only occurs if the cells have been stimulated to have a respiratory burst. These observations have obvious possible implications for the mechanism of procainamide-induced agranulocytosis (formation of a reactive metabolite by neutrophils) and procainamide-induced lupus (formation of a reactive metabolite by monocytes). The metabolism of drugs to reactive metabolites by monocytes may be a general mechanism for hypersensitivity reactions because monocytes play a key role in the processing of antigen and stimulation of antibody synthesis.

Biotransformation↗
PubMedDate not supplied

N-chlorination of phenytoin by myeloperoxidase to a reactive metabolite.

Several types of phenytoin toxicity appear to involve leukocytes. We had previously demonstrated that other drugs were metabolized to reactive metabolites by activated neutrophils and monocytes or the combination of myeloperoxidase (MPO) and hydrogen peroxide. In this study we found that phenytoin was chlorinated by MPO/H2O2/Cl- to N,N'-dichlorophenytoin which is chemically reactive. Failure to demonstrate that activated neutrophils also formed N,N'-dichlorophenytoin appeared to be due to the rapid reaction of N,N'-dichlorophenytoin with neutrophils. We were able to demonstrate that phenytoin covalently bound to albumin in the presence of MPO/H2O2/Cl- and to neutrophils, but only if the cells were activated. Such activation leads to the release of MPO and the generation of H2O2. We, therefore, speculate that the toxicity of phenytoin may be due to the formation of N,N'-dichlorophenytoin by activated neutrophils or monocytes.

Biotransformation↗
PubMedDate not supplied

Comparative metabolism and covalent binding of procainamide by human leukocytes.

Activated neutrophils and monocytes were found to metabolize procainamide to a reactive hydroxylamine. In contrast, there was little or no metabolism by lymphocytes or platelets. Therefore, it appears that only leukocytes that contain myeloperoxidase can metabolize procainamide to a significant degree. There was no difference in the degree to which neutrophils from males or females metabolized procainamide; however, monocytes from males formed significantly more hydroxylamine than did monocytes from females. By use of radiolabeled procainamide, covalent binding of procainamide to leukocytes was detected, and the degree of binding correlated with the cells' ability to oxidize procainamide. These findings suggest that myeloperoxidase is the major enzyme involved in the formation of reactive metabolites by leukocytes, a pathway that we propose may be responsible for procainamide-induced lupus and agranulocytosis.

Binding Sites↗
PubMedDate not supplied

Oxidation of propylthiouracil to reactive metabolites by activated neutrophils. Implications for agranulocytosis.

Propylthiouracil (PTU) is associated with idiosyncratic agranulocytosis that may be due to reactive metabolites generated from oxidative metabolism by neutrophils. Therefore, the metabolism of PTU was investigated in activated neutrophils. Three oxidized metabolites were observed on HPLC: PTU-disulfide, propyluracil-2-sulfinate, and propyluracil-2-sulfonate (PTU-SO3-). No metabolism was detected in cells that had not been activated. Metabolism was inhibited by sodium azide and by catalase. The same products were produced by myeloperoxidase (MPO) in an MPO/H2O2/Cl- system. PTU inhibited its own metabolism; however, complete conversion to PTU-SO3- could be achieved with optimal PTU concentrations. MPO/H2O2 without Cl- produced only slight metabolism. The PTU-sulfenyl chloride is a postulated intermediate. In the absence of chloride, oxidation might proceed through propyluracil-2-sulfenic acid. The sulfenyl chloride and PTU-SO3- are both chemically reactive with sulfhydryl compounds such as N-acetylcysteine. Such reactive metabolites, generated by activated neutrophils, may be involved in hypersensitivity reactions associated with PTU, such as agranulocytosis.

Agranulocytosis↗