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At least 19 recordsLinked to original sources

PubMed1981

Metabolite pharmacokinetics: the area under the curve of metabolite and the fractional rate of metabolism of a drug after different routes of administration for renally and hepatically cleared drugs and metabolites.

A model comprised of four compartments, a central and liver compartment for a drug, and a central and liver compartment for a metabolite, is presented to describe the interrelationships between the area under the curve of the metabolite and physiological parameters after intravenous and intraportal administration of the drug. The model includes renal and hepatic eliminatory mechanisms for both drug and metabolite as long as the metabolite is formed only by the liver. It is found that when competing renal eliminatory pathways exist for a drug, the area under the curve for the metabolite will change according to the route of drug administration. Also, the fractional rate of metabolism of a drug to form the metabolite will be underestimated by the normal use of the ratio areas under the curve of the metabolite. Other properties of the model are also discussed.

Animals↗

PubMed1982

Influence of 15-keto-metabolites and 13,14-dihydro-15-keto-metabolites of PGE2 and PGF2 alpha as well as of 6-keto-PGF1 alpha as a metabolite of PGI2 on aconitine induced cardiac arrhythmia in rats.

The 15-keto-metabolites of PGE2 and PGF2 alpha produced an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 values of these metabolites were approximately 2.0 micrograms/kg. The 13,14-dihydro-15-keto-metabolites of PGE2 and PGF2 alpha had no statistically significant antiarrhythmic effect. PGI2 (0.25-1.00 micrograms/kg) produced an antiarrhythmic effect between 15-54% (ED50 0.75 micrograms/kg), whereas 6-keto-PGF1 alpha, a metabolite of PGI2, showed no significant antiarrhythmic effect. The results suggest a participation of 15-keto-metabolites in the antiarrhythmic effects of PGE2 and PGF2 alpha.

Aconitine↗

PubMed1990

Validity testing of commercial urine cocaine metabolite assays: IV. Evaluation of the EMIT d.a.u. cocaine metabolite assay in a quantitative mode for detection of cocaine metabolite.

The EMIT d.a.u. cocaine metabolite assay (EMIT dau) was evaluated in a quantitative mode for analysis of clinical specimens obtained after controlled cocaine administration to human subjects. The quantitative results showed high concordance with those of gas chromatography/mass spectrometry (GC/MS) assays of the same specimens for benzoylecgonine, and no false positive or false negative results were obtained. The evaluation also included analysis of standardized solutions containing benzoylecgonine, cocaine, and other cocaine metabolites and isomers. The EMIT dau antibody demonstrated high selectivity for benzoylecgonine. The precision was somewhat less than that reported earlier for other commercial cocaine metabolite immunoassays. Quantitation of initial screening results from EMIT dau testing can serve as a useful guide for confirmation by GC/MS in forensic science urine testing.

Cocaine↗

PubMed2005

Biomarker metabolites capturing the metabolite variance present in a rice plant developmental period.

BACKGROUND: This study analyzes metabolomic data from a rice tillering (branching) developmental profile to define a set of biomarker metabolites that reliably captures the metabolite variance of this plant developmental event, and which has potential as a basis for rapid comparative screening of metabolite profiles in relation to change in development, environment, or genotype. Changes in metabolism, and in metabolite profile, occur as a part of, and in response to, developmental events. These changes are influenced by the developmental program, as well as external factors impinging on it. Many samples are needed, however, to characterize quantitative aspects of developmental variation. A biomarker metabolite set could benefit screening of quantitative plant developmental variation by providing some of the advantages of both comprehensive metabolomic studies and focused studies of particular metabolites or pathways. RESULTS: An appropriate set of biomarker metabolites to represent the plant developmental period including the initiation and early growth of rice tillering (branching) was obtained by: (1) determining principal components of the comprehensive metabolomic profile, then (2) identifying clusters of metabolites representing variation in loading on the first three principal components, and finally (3) selecting individual metabolites from these clusters that were known to be common among diverse organisms. The resultant set of 21 biomarker metabolites was reliable (P = 0.001) in capturing 83% of the metabolite variation in development. Furthermore, a subset of the biomarker metabolites was successful (P = 0.05) in correctly predicting metabolite change in response to environment as determined in another rice metabolomics study. CONCLUSION: The ability to define a set of biomarker metabolites that reliably captures the metabolite variance of a plant developmental event was established. The biomarker metabolites are all commonly present in diverse organisms, so studies of their quantitative relationships can provide comparative information concerning metabolite profiles in relation to change in plant development, environment, or genotype.

Amino Acids↗

PubMed1991

Investigations on the metabolic pathways of cyclosporine: I. Excretion of cyclosporine and its metabolites in human bile--isolation of 12 new cyclosporine metabolites.

1. Cyclosporine metabolites of known and unknown structures were isolated, by semi-preparative h.p.l.c., from human bile from the T-tube of liver-grafted patients, who received cyclosporine treatment. Their structures were elucidated by FAB mass spectrometry and 1H-n.m.r. spectroscopy. 2. Twelve of the cyclosporine metabolites, with known chemical structures, were isolated and identified using authentic standard material. 3. Four isolated fractions contained tri-hydroxylated metabolites; two fractions contained di-hydroxylated, demethylated metabolites; one fraction contained a tri-hydroxylated, demethylated metabolite; and one fraction a mono-hydroxylated, demethylated metabolite. The exact metabolism sites were partially defined. 4. Two carboxylated cyclosporine metabolites, of which one was hydroxylated in an unknown position, were isolated. 5. One new metabolite proved to be a glucuronylated phase II metabolite. Deglucuronylation of this metabolite by beta-glururonidase yielded metabolite AM1c. The proposed structure was AM1c-Glc; is a proposed extension of the Hawk's Cay nomenclature of the cyclosporine metabolites for glucuronylated metabolites. 6. One of the unknown metabolites was hydroxylated in two positions of amino acid 1. The proposed nomenclature was 'AM11d', where '1d' indicates hydroxylation at the delta C of amino acid 1. 7. A metabolite with an aldehyde functional group at amino acid 1, which had two isomeric forms, was isolated. I.r.-spectroscopy indicated that isomerism may be caused by conjugation of the aldehyde group with the double bond between C6 and C7 of amino acid 1.

Aldehydes↗

PubMed1992

Polar metabolites of dihydrotachysterol3 in the rat. Comparison with in vitro metabolites of 1 alpha,25-dihydroxydihydrotachysterol3.

The metabolism of 25-hydroxydihydrotachysterol3 (25-OH-DHT3) to more polar metabolites was investigated in vivo in the rat and compared with the in vitro metabolism of 1 alpha,25-dihydroxy-DHT3 (1 alpha,25-(OH)2DHT3) in the osteosarcoma cell line UMR 106. Rats were given 2 mg of DHT3 in divided doses at 0 and 6 hr. Plasma was collected 24 hr after the initial dose, extracted, separated, and polar metabolites purified by HPLC. A number of polar metabolites were formed in vivo with mass spectrometric characteristics which suggested that they were derived from a previously isolated metabolite of 25-OH-DHT3, T3/H. Of these, four were isolated and identified as 24-oxo-T3/H, 24-hydroxy-T3/H, 26-hydroxy-T3/H and the 26,23-lactone of T3/H. In view of the identification of T3/H as a mixture of 1 alpha- and 1 beta-hydroxylated 25-OH-DHT3, osteosarcoma cells (UMR 106) were incubated with chemically synthesized 1 alpha,25-(OH)2DHT3 in an attempt to determine from which component of the T3/H mixture these metabolites were derived. Again, more polar metabolites were formed and five of these were isolated by lipid extraction, purified by HPLC and identified as 24-oxo-1 alpha,25-(OH)2DHT3, 1 alpha,23,25-(OH)3DHT3, 24-oxo-1 alpha,23,25-(OH)3DHT3, 1 alpha,24,25-(OH)3DHT3 and 1 alpha,25,26-(OH)3DHT3. Three of the in vitro metabolites were similar to those found in rat plasma but only two of these metabolites were available in sufficient amounts to allow comparison. The chromatographic characteristics, using HPLC and gas chromatography, of these two pairs of metabolites (24-oxo and 24-hydroxy) were examined and it was demonstrated that they were not the same. It is therefore suggested that the polar metabolites formed in vivo are in fact metabolites of the T3/Hb component (1 beta,25-(OH)2DHT3) rather than the T3/Ha component (1 alpha,25-(OH)2DHT3). Supporting evidence for this suggestion was obtained when a small quantity of 1 beta,25-(OH)2DHT3, obtained from chemically synthesized 1 beta-OH-DHT3 by incubation with Hep 3B cells, was further incubated in the osteosarcoma UMR 106 system. Preliminary studies indicated that the putative 24-oxo and 24-hydroxy metabolites formed from 1 beta,25-(OH)2DHT3 had chromatographic and mass spectral properties almost indistinguishable from those of corresponding metabolites of T3/H formed in vivo. All the metabolites formed in vivo and in vitro are components of two metabolic pathways described previously for 25-hydroxyvitamin D3 and also for 25-OH-DHT3.

Animals↗

PubMed2003

Identification of nitric oxide metabolites in various honeys: effects of intravenous honey on plasma and urinary nitric oxide metabolites concentrations.

Honey has antibacterial activity, promotes healing, and enhances immunity. Its acidity, osmotic effects of its high content of sugar, and hydrogen peroxide are assumed to be responsible for its effects. In this study, various honeys were investigated for the presence of nitrite/nitrate, the stable nitric oxide (NO) metabolites, and the effects of intravenous infusion of honey on urinary and plasma NO end products were studied in healthy sheep. Seven kinds of honey, different in their origin (three from Yemen, two from the United Arab Emirates, one from Germany, and one from India), color, and duration of storage, were investigated for the presence of NO metabolites. The assessment of NO metabolites was performed before and after exposure of the honey samples to heating (80 degrees C for 1 hour) or ultraviolet light (for 24 hours). Seven healthy male sheep were used for the study. Fresh unprocessed yellow honey (2 g/kg of body weight) was infused over a period of 45 minutes to each fasting sheep. Plasma and urinary NO metabolites were measured before and after the infusion. All the honey samples examined had various concentrations of NO metabolites; the highest concentration was in the fresh dark honey collected from Yemen, and the lowest in 1-year-stored dark honey collected from India. Darker or fresh honeys contained more NO metabolites than light or stored honey. After heating, NO metabolites decreased in all the kinds of honey. After ultraviolet exposure, NO metabolites were decreased in four kinds of honey, increased in one kind, and unchanged in two kinds. The darker stored honey had more resistance to heating and ultraviolet exposure. Intravenous infusion of honey elevated urinary NO metabolites from 8.4 +/- 7.4 micromol/L to 14.9 +/- 10 micromol/L during the first 60-90 min after infusion and to 35.2 +/- 34 micromol/L during the next 150-180 min. Plasma NO metabolites were increased during 1, 2, and 3 hours after infusion by 3%, 3.6%, and 17%, respectively. No side effects were reported with the use of intravenous honey. It might be concluded that honey contains various concentrations of NO metabolites. Its intravenous infusion increased plasma and urinary NO metabolites. It is assumed that NO might be responsible, in part, for the biological and therapeutic effects of honey.

Analysis of Variance↗

PubMed2006

Complicating factors in safety testing of drug metabolites: kinetic differences between generated and preformed metabolites.

This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.

Animals↗

PubMed2006

Metabolite projection analysis for fast identification of metabolites in metabonomics. Application in an amiodarone study.

The assignment of significantly changed NMR signals, which were identified with the help of multivariate models, to individual metabolites in biofluids is a manual and tedious task requiring knowledge in chemometrics and NMR spectroscopy. Metabolite projection analysis, introduced in this work, allows automatic linking of multivariate models with metabolites by skipping the level of manual NMR signal identification. The method depends on the projection of sets of metabolite NMR spectra from a database into PCA or PLS models of NMR spectra of biofluid samples. Metabolites that are significantly changed can be identified graphically in metabolite projection plots or numerically as projected virtual concentration. The method is demonstrated together with a newly introduced algorithm for refined nonequidistant binning using a metabonomics study with amiodarone as administered drug. Amiodarone can induce phospholipidosis in the lung and liver, which is accompanied by associated organ toxicity in these organs. It is shown how metabolite projection analysis allows easy and fast tentative assignment of all structures of metabolites whose concentrations in the urine samples significantly changed upon dosage. These metabolites had also been identified previously by manually interpreting the multivariate models and spectra. Among these metabolites, phenylacetylglycine was also identified as being significantly increased. This metabolite has recently been proposed as urinary biomarker for phospholipidosis.

Amiodarone↗

PubMed2005

Structural elucidation of human oxidative metabolites of muraglitazar: use of microbial bioreactors in the biosynthesis of metabolite standards.

Muraglitazar (Pargluva), a dual alpha/gamma peroxisome proliferator-activated receptor activator, is currently in clinical development for treatment of type 2 diabetes. This study describes the structural elucidation of the human oxidative metabolites of muraglitazar through the use of a combination of microbial bioreactors, NMR and accurate mass analyses, and organic synthesis. Plasma, urine, and feces were collected from six healthy subjects following oral administration of 14C-labeled muraglitazar (10 mg, 100 microCi) and pooled samples were analyzed. Approximately 96% of the recovered radioactive dose was found in the feces and 3.5% in the urine. The parent compound represented >85% of the radioactivity in plasma. The fecal radioactivity was distributed among 16 metabolites (M1-M12, M14-M16, and M8a) and the parent drug, of which hydroxylation and O-demethylation metabolites (M5, M10, M11, M14, and M15) represented the prominent human metabolites. The urinary radioactivity was distributed into several peaks including muraglitazar glucuronide (M13) and the parent drug. Low concentrations of metabolites in human samples prevented direct identification of metabolites beyond liquid chromatographic (LC)-mass spectrometric analysis. Microbial strains Cunninghamella elegans and Saccharopolyspora hirsuta produced muraglitazar metabolites that had the same high performance liquid chromatography retention times and the same tandem mass spectrometric (MS/MS) properties as the corresponding human metabolites. The microbial metabolites M9, M10, M11, M14, M15, and M16 were isolated and analyzed by NMR. Based on these LC-MS/MS and NMR analyses, and organic synthesis, the structures of 16 human oxidative metabolites were identified. The oxidative metabolism of muraglitazar was characterized by hydroxylation, O-demethylation, oxazolering opening, and O-demethylation/hydroxylation, as well as O-dealkylation and carboxylic acid formation. This study demonstrated the utility of microbial bioreactors for the identification of metabolites.

Bioreactors↗

PubMed1999

Metabolites of mercaptopurine in red blood cells: a relationship between 6-thioguanine nucleotides and 6-methylmercaptopurine metabolite concentrations in children with lymphoblastic leukemia.

Intracellular concentrations of 6-mercaptopurine metabolites, i.e. of 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) were analysed in red blood cells (RBC) of 19 children with acute lymphoblastic leukemia (ALL), the subjects of a maintenance chemotherapy of their first remission. Interpatient variations in concentrations of both metabolites were high; concentrations of 6-TGN varied from <60 to 833 pmol/8x10(8) RBC (median value, 144) and those of 6-mMP metabolites from <150 to 19000 pmol/8x10(8) RBC (median value, 3250). In two patients, 6-TGN appeared at concentrations below the limits of assay sensitivity, and 6-mMP metabolites were not detected. In another child the concentrations of both metabolites were at the limit of the assay sensitivity. In three other children the concentrations of both metabolites were below the median value of the group. In the analysed group of children, significant correlations were found between the white cell count (WBC) and RBC 6-TGN (r(s)=-0.72, P<0. 005) as well as between the neutrophil count and RBC 6-TGN (r(s)=-0.60, P<0.01). No significant correlation was found between the concentrations of 6-TGN and 6-mMP metabolites. The monitoring of concentrations of 6-TGN as well as of 6-mMP metabolites allows an early identification of patients who are at an increased risk of the disease relapse as indicated by the low levels of either 6-TGN itself or of its two metabolites.

Adolescent↗

PubMed1988

Metabolite formation pharmacokinetics: rate and extent of metabolite formation determined by deconvolution.

A two-step analytic procedure to determine the rate and extent of metabolite production following administration of the parent compound is described. The procedure provides the rate and extent of metabolite production as a function of time by application of the general model independent approach of deconvolution. The metabolite unit impulse response function is obtained by implicit deconvolution of the metabolite data with a truncated constant-rate metabolite input function. Then the obtained unit impulse response function is used in an analytic deconvolution with metabolite data following administration of the parent compound to obtain the rate and extent of metabolite production. The input function is also deconvolved with metabolite data to obtain the unit impulse response function appropriate for prediction of metabolite levels given a selected input of parent compound. The expected profile following administration of the consecutive infusions of parent drug is shown for both parent and metabolite. The rationale for selection of deconvolution methods is discussed. The approach is applied to data for procainamide and N-acetylprocainamide from three human subjects. The results indicate that from 27 to 39% of the procainamide was converted to N-acetylprocainamide in these subjects.

Acecainide↗

PubMedDate not supplied

Valproate metabolites in serum and urine during antiepileptic therapy in children with infantile spasms: abnormal metabolite pattern associated with reversible hepatotoxicity.

The purpose of this study was to identify abnormal metabolite patterns of valproate (VPA) as possible early indicators of VPA-induced liver toxicity. In a prospective study, we determined serum and urine levels of VPA metabolites by gas chromatography-mass spectrometry (GC-MS) during the course of therapy in 25 children treated for infantile spasms with high VPA doses (less than or equal to 100 mg/kg body weight/day). Most patients had similar metabolite profiles: The main metabolites in serum were the beta-oxidation products (2-en-VPA and 3-keto-VPA) and the major diunsaturated metabolite 2,3'-dien-VPA. Glucuronide conjugates and the oxidation products represent the most abundant metabolites in urine. Other metabolites, including the potential hepatotoxin 4-en-VPA, were detected only in low concentrations. Two children had transiently aberrant metabolite profiles, indicating altered beta-oxidation, (levels of 2-en-VPA, 2,3'-dien-VPA, and 3-en-VPA were markedly increased) in connection with hepatomegaly and increased liver enzyme activities at a time when both had febrile infections and were receiving dexamethasone comedication. At no time were increased levels of 4-en-VPA or its derivatives detected. Establishing the VPA metabolite profile may aid in evaluation of patients who show signs and symptoms of liver dysfunction during VPA therapy. The present study shows that initial stages of hepatotoxicity reactions to VPA may be accompanied by characteristic changes in VPA metabolism; early detection of such abnormal metabolite patterns might decrease the risk of severe hepatic injury.

Chemical and Drug Induced Liver Injury↗

PubMed1991

Identification of cannabichromene metabolites by mass spectrometry: identification of eight new dihydroxy metabolites in the rabbit.

Metabolites of cannabichromene (CBC) produced by hepatic microsomal incubates from rabbits and mice were examined by gas chromatography/mass spectrometry (GC/MS) as trimethylsilyl (TMS) and (2H9)TMS derivatives. Most metabolites were hydroxylated compounds whose mass spectra gave very little information on metabolite structure as fragmentation was dominated by formation of the substituted chromenyl ion. This prevented charge localization and diagnostic fragmentation at the site of metabolic attack. This paper describes the identification of these metabolites by GC/MS techniques using both deuterium-exchange reactions and hydrogenation of the metabolites to tetrahydro derivatives; the latter method was used to suppress chromenyl ion formation and to enhance the relative abundance of diagnostic fragment ions. Twenty-one metabolites were identified. Metabolites were found hydroxylated in all positions of both aliphatic chains, with additional compounds formed by epoxidation and reduction of the aliphatic double bond in the methylpentenyl chain. Dihydroxy metabolites were hydoxylated in both the pentyl and methylpentenyl chains in positions common to those hydroxylated in the monohydroxy metabolites.

Animals↗

PubMed1994

Species differences in urinary butadiene metabolites: comparisons of metabolite ratios between mice, rats, and humans.

We have previously identified two metabolites, 1,2-dihydroxy-4-(N-acetylcysteinyl-S-)-butane (M-I) and 1-hydroxy-2-(N-acetylcysteinyl-S-)-3-butene (M-II) in the urine of mice, rats, hamsters, and monkeys exposed by inhalation to 8000 ppm [14C]butadiene. The sum of these two metabolites constituted between 50 and 90% of the total urinary [14C]butadiene equivalents. When comparing species, the ratios of excreted M-I relative to the total of M-I + M-II were linearly related to hepatic epoxide hydrolase activities, with mice displaying the lowest ratios and monkeys displaying the highest ratios. Because humans are known to have epoxide hydrolase activities more similar to those of monkeys than mice, we postulated that after inhalation of butadiene, humans would excrete predominantly M-I and little M-II. To address this hypothesis, we measured the two metabolites in the urine of workers occupationally exposed to butadiene. We initially developed an assay to measure the two metabolites in urine using techniques not dependent on radiolabeled compounds. The assay is based on isotope-dilution gas chromatography/mass spectroscopy. After addition of deuterated internal standards, the metabolites were isolated from urine samples by solid-phase extraction and selective precipitation. The metabolites were converted to volatile derivatives by trimethylsilylation prior to analysis. The assay is sensitive down to at least 100 ng/ml of both metabolites in urine. The assay was applied to urine samples of humans occupationally exposed to butadiene in a production plant. M-I, but not M-II, could be readily identified and quantitated in the urine samples at levels frequently greater than 1 microgram/ml, thus supporting our hypothesis. Employees who worked in production areas with historical atmospheric concentrations of 3-4 ppm butadiene could be distinguished as a group from those outside controls. Finally, mice and rats were exposed to 11.7 ppm butadiene for 4 hr, and the ratio of the two metabolites was measured. For mice, the ratios of M-I to M-I + M-II were similar to those reported previously following exposure to 8000 ppm. In contrast, for rats, M-I represented a higher proportion of the excreted metabolites at the lower exposure level. These results confirm earlier in vitro studies that suggested the predominant pathway for clearance of BDO in humans is by hydrolysis rather than direct conjugation with glutathione.

Acetylcysteine↗

PubMed2002

Drug and chemical metabolites in clinical toxicology investigations: the importance of ethylene glycol, methanol and cannabinoid metabolite analyses.

Metabolic pathways in humans have been elucidated for most therapeutic drugs, drugs of abuse, and various chemical/solvents. In most drug overdose cases and chemical exposures, laboratory analysis is directed toward identification and quantitation of the unchanged drug or chemical in a biologic fluid such as serum or whole blood. Specifically, most clinical laboratories routinely screen and quantitate unchanged methanol and/or ethylene glycol in suspected poisonings without toxic metabolite analysis. Martin-Amat established in 1978 that methanol associated toxicity to the optic nerve in human poisonings was due to the toxic metabolite formic acid found in methanol poisonings and not due to the direct action by unchanged methanol. Jacobsen reported in 1981 that ethylene glycol central nervous system and renal toxicity were primarily due to one acidic metabolite (glycolic acid) and not due to unchanged ethylene glycol. The first objective of this review is to describe clinical experience with formic acid and glycolic acid analysis in methanol and ethylene glycol human poisonings. Drug metabolite analysis also provides useful information in the assessment and monitoring of drug use in psychiatry and substance abusing populations. Drug analysis in substance abuse monitoring is focused on urine analysis of one or more major metabolites, and less frequently on the unchanged drug(s). Serial monitoring of the major urinary cannabinoid metabolite (delta(9)-THC-COOH) to creatinine ratios in paired urine specimens (collected at least 24 h apart) could differentiate new marijuana or hashish use from residual cannabinoid metabolite excretion in urine after drug use according to Huestis. The second objective is to demonstrate that creatinine corrected urine specimens positive for cannabinoids may help differentiate new marijuana use from the excretion of residual delta(9) -THC-COOH in chronic users of marijuana or hashish. Analysis of toxic chemical metabolites are helpful in the assessment and treatment of chemical poisoning whereas serial monitoring of urinary cannabinoid metabolites are predictive of illicit drug use in the substance abusing population.

Cannabinoids↗

PubMed2001

In vitro nephrotoxicity induced by N-(3,5-dichlorophenyl)succinimide (NDPS) metabolites in isolated renal cortical cells from male and female Fischer 344 rats: evidence for a nephrotoxic sulfate conjugate metabolite.

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in vivo that is characterized as acute polyuric renal failure and proximal tubular necrosis. However, earlier in vitro studies have failed to reproduce the in vivo nephrotoxicity seen with NDPS or its nephrotoxic metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA). The purpose of this study was to examine the nephrotoxic potential of NDPS, its known non-conjugated metabolites, the O-sulfate conjugate of NDHS (NSC), and the putative metabolite N-(3,5-dichlorophenyl)maleimide (NDPM) and its hydrolysis product N-(3,5-dichlorophenyl)maleamic acid (NDPMA) using freshly isolated renal cortical cells (IRCC). IRCC were obtained from untreated male or female Fischer 344 rats following collagenase perfusion of the kidneys. Cells (approximately 4 million per ml) (N=4) were incubated with up to 1.0 mM NDPS or an NDPS metabolite or vehicle for up to 120 min. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release into the medium. Only NSC (>0.5 mM) and NDPM (> or =0.5 mM) exposure increased LDH release from IRCC. NSC 1.0 mM or NDPM 0.5 mM increased LDH release from IRCC within 15--30 min of exposure. NDPS or the remaining NDPS metabolites did not increase LDH release at bath concentrations of 1.0 mM for exposures of 120 min. IRCC from male and female rats responded similarly to the toxic effects of NDPS and its metabolites. These results demonstrate that sulfate conjugates of NDPS metabolites can be fast acting nephrotoxicants and could contribute to NDPS nephrotoxicity in vivo. These results also suggest that the kidney probably accumulates toxic sulfate conjugates of NDPS metabolites rather than forming the conjugates. In addition, mechanisms responsible for gender differences in nephrotoxicity seen with NDPS and NDPS metabolites in vivo either occur prior to renal accumulation of sulfate conjugates and/or represent biochemical/physiological differences between the genders.

Animals↗

PubMed1996

Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients.

1. Six male and six female stable renal allograft recipients under cyclosporine immunosuppression and without concomitant therapy with drugs known either to induce or inhibit CYP3A enzymes were included in the study and received 180 mg day-1 diltiazem for 1 week in a two-period cross-over fashion. Cyclosporine (352 +/- 56 mg day-1) was given in two daily oral doses. The daily doses were not changed during the study. Blood samples were collected for 12 h after receiving cyclosporine alone and after receiving diltiazem in addition for 1 week. Cyclosporine and nine of its metabolites were quantified using h.p.l.c. 2. Co-administration of diltiazem caused a 1.6 fold increase of the AUC (0, 12 h) of cyclosporine and a 1.7 fold increase of the AUC(0, 12 h) of its metabolites. Analysis of the metabolite patterns showed an over-proportional increase of the AUC(0, 12 h) of the cyclized metabolites AM1c (2.6 fold) and AM1c9 (2.2 fold). The AUC(0, 12 h) values of cyclosporine and the hydroxylated metabolites increased less than two fold. 3. Differences of the AUC(0, 12 h) values of cyclosporine with and without diltiazem were significantly higher in female than in male patients (P < 0.02). The differences in the AUC(0, 12 h) values of the metabolites, especially AM1c, tended to be higher in female patients as well. 4. It is concluded that coadministration of diltiazem not only increases the blood concentration of cyclosporine but also those of its metabolites, leads to a shift of the metabolite pattern towards cyclized metabolites, and that the pharmacokinetic changes under diltiazem administration are more prominent in female than in male patients.

Adult↗