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1.
Clin Pharmacol Ther ; 70(2): 183-8, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11503013

ABSTRACT

Thiopurine S-methyltransferase (TPMT) activity exhibits genetic polymorphism. The purpose of this investigation was to identify TPMT mutant alleles in the Saami population as a basis of developing genotyping tests for prediction of TPMT activity. The most predominant allele in Saamis (n = 194) was the TPMT*3C allele (A719G mutation) representing 92% of the mutant alleles, with an estimated allelic frequency of 3.3%. The most frequent allele in Caucasians (n = 66) living in the same geographic area was the TPMT*3A (A719G and G460A mutations) representing 91% of the mutant alleles, with an estimated allelic frequency of 3.4%. A test for one mutation, A719G, may prospectively identify more than 90% of the Saami individuals who require reduction in thiopurine dose to avoid hematopoietic toxicity. In a Norwegian population, comprising both the major Caucasian population and a minor Saami population, the same genotyping tests (eg, tests for the A719G and G460A mutations) may be used.


Subject(s)
Methyltransferases/genetics , Mutation , White People/genetics , Adult , Alleles , Female , Genotype , Humans , Male , Methyltransferases/metabolism , Norway/ethnology , Phenotype , Polymorphism, Genetic , Sequence Analysis, DNA
3.
Scand J Clin Lab Invest ; 61(3): 217-25, 2001 May.
Article in English | MEDLINE | ID: mdl-11386608

ABSTRACT

BACKGROUND: Protein S-100beta is an established biochemical marker for cerebral injury in serum. For the further interpretation and possible use of S-100beta serum measurements in acute hepatic encephalopathy, renal elimination of S-100beta was measured in pigs with elevated S-100beta levels due to hepatic encephalopathy. METHODS: Eighteen female Norwegian Landrace pigs were randomly allocated to either hepatic devascularization (n=13) or sham operation (n=5). Repeated samples from the common carotid artery, right renal vein, and urine were simultaneously drawn for S-100beta analysis, using the Sangtec100 Liamat immunoassay. RESULTS: In hepatic devascularized pigs, arterial serum levels of S-100beta increased from 0.96+/-0.04 microg/L (mean +/- SEM) at t = 0h to 1.74+/-0.11 microg/L (mean +/- SEM) at t = 5 h. Urinary excretion increased simultaneously from 8.48+/-3.66 ng/h (mean +/- SEM) to 20.4+/-9.54 ng/h (mean +/- SEM), while renal arterial-venous fluxes for both kidneys increased from 1022+/-404 ng/h (mean +/- SEM) to 2444+/-590 ng/h (mean +/- SEM). CONCLUSIONS: Increased arterial S-100beta levels in pigs with acute hepatic encephalopathy are not a result of decreased renal elimination. The large difference between the renal arterial venous S-100beta concentrations and the urinary excretion of S-100beta indicate that renal metabolism is the major route of elimination.


Subject(s)
Hepatic Encephalopathy/diagnosis , Kidney/metabolism , S100 Proteins/blood , S100 Proteins/urine , Acute Disease , Animals , Biomarkers , Female , Hepatic Encephalopathy/blood , Hepatic Encephalopathy/urine , Kidney/blood supply , Liver Failure/blood , Liver Failure/diagnosis , Liver Failure/urine , Nerve Growth Factors , Renal Artery , Renal Circulation , S100 Calcium Binding Protein beta Subunit , Swine
4.
Biochem Pharmacol ; 61(6): 707-14, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11266655

ABSTRACT

The susceptibility of recombinant human thiopurine methyltransferase (hTPMT) to thiol-disulfide exchange was investigated. The enzyme was incubated in buffers of the redox couple GSH and GSSG. The values of the chosen concentrations and concentration ratios of the redox couple equaled those expected to occur in vivo. Activity measurements of the enzyme over time in these buffers at 30 degrees C indicated that thiol-disulfide exchange may be a part of the posttranslational modulation of hTPMT activity. Activity varied between 5% and 100%, with the lowest activities in buffers of low [GSH]/[GSSG] concentration ratios and of low total concentration of the redox couple. A thiol-disulfide exchange mechanism involving a mixed disulfide was proposed. Titration of the protein thiol groups with Ellmann's reagent (5,5'-dithiobis[2-nitrobenzoic acid]) revealed that at least two protein thiols were readily accessible for conjugation with the reagent, while others were conjugated more slowly. The previous model of hTPMT constructed by our group was in accordance with the experimental results. Inspection of the model indicated that one of the protein thiols subject to slow thiol-disulfide exchange may be situated at the binding site of the co-substrate of the enzyme and thus be responsible for the glutathione/glutathione disulfide modulation of the activity of hTPMT.


Subject(s)
Glutathione Disulfide/metabolism , Glutathione/metabolism , Mercaptopurine/metabolism , Methyltransferases/metabolism , Buffers , Computer Simulation , Humans , Methyltransferases/chemistry , Models, Molecular , Oxidation-Reduction , Recombinant Proteins/metabolism , Sulfhydryl Compounds/analysis , Titrimetry
6.
Pediatr Hematol Oncol ; 17(8): 651-8, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11127396

ABSTRACT

High-dose methotrexate (HD-MTX) is widely used in combination chemotherapy and can be handled without life-threatening toxicity in combination with leucovorin (LV) rescue. However, in an experimental animal model for testing of short-term HD-MTX effects in anesthetized rats, the authors previously demonstrated intolerable toxicity and death within a few hours in some animals. Serum levels were below levels routinely found in patients on HD-MTX treatment. This study was aimed at disclosure of possible mechanisms for acute toxicity of MTX in rats. The previously determined maximum tolerated dose of 5 g/kg MTX was used as the test dose. The animals that died showed sudden reduction in heart rate and blood pressure. LV, 1 g/kg infused immediately prior to MTX, changed MTX elimination kinetics, but did not change the acute toxicity. The data of this study together with additional evidence obtained in the experimental model, suggest that MTX acute toxicity may not be related to its antiproliferative effect, but rather to perturbation of endothelial cell and platelet function.


Subject(s)
Antimetabolites, Antineoplastic/toxicity , Leucovorin/pharmacology , Maximum Tolerated Dose , Methotrexate/toxicity , Animals , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/blood , Arrhythmias, Cardiac/chemically induced , Kidney/drug effects , Liver/drug effects , Male , Methotrexate/administration & dosage , Methotrexate/blood , Rats , Rats, Wistar , Survival Rate
8.
Ultrastruct Pathol ; 24(5): 325-32, 2000.
Article in English | MEDLINE | ID: mdl-11071571

ABSTRACT

Methotrexate (MTX) is a clinically important cytostatic antifolate. The study describes the acute effects of maximum tolerated doses of MTX or its major metabolite 7-hydroxymethotrexate (7-OH-MTX) on the ultrastructure of rat liver and kidneys. The ultrastructural changes in rats receiving MTX or 7-OH-MTX were, in principle, indistinguishable and their severity and extension increased with time of survival or doses of medication. All lesions were focal, microvascular, or parenchymal. Microvascular changes were more severe in nature when blood cells were present. The endothelial cells were swollen with loss of pinocytotic vesicles, their luminal plasma membrane formed blebs or were disrupted. Partly detached endothelial cells or deendothelialized areas, various types of white blood cells, in particular, neutrophil granulocytes, were observed in the microcirculation. Single platelets or small platelet aggregates were found either in the lumen or adhering to deendothelialized areas of injured endothelial cells. Hepatocytes exhibited steatosis, edema, and manifest single cell necrosis. There were also nuclear changes, marked proliferation of smooth endoplasmatic reticulum, increased amounts of intracellular lipid vacuoles, and a decrease in glycogen particles in hepatocytes. The kidney presented the major changes in the tubules and in the interstitial part. MTX and 7-OH-MTX acute toxicity may primarily be related to microvascular perturbation.


Subject(s)
Antineoplastic Agents/toxicity , Endothelium, Vascular/drug effects , Kidney/blood supply , Liver/blood supply , Methotrexate/toxicity , Animals , Dose-Response Relationship, Drug , Endothelium, Vascular/ultrastructure , Hepatocytes/drug effects , Hepatocytes/ultrastructure , Kidney/ultrastructure , Liver/ultrastructure , Male , Maximum Tolerated Dose , Methotrexate/analogs & derivatives , Microcirculation/drug effects , Microcirculation/ultrastructure , Rats , Rats, Wistar
9.
Cancer Chemother Pharmacol ; 46(1): 69-73, 2000.
Article in English | MEDLINE | ID: mdl-10912581

ABSTRACT

PURPOSE: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD(50) for reasons of animal welfare. METHODS: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8 11.3 g/kg MTX and 0.1-1.2 g/kg 7-OH-MTX. RESULTS: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. CONCLUSIONS: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.


Subject(s)
Methotrexate/analogs & derivatives , Methotrexate/toxicity , Animals , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Electrocardiography/drug effects , Heart Rate/drug effects , Male , Methotrexate/administration & dosage , Methotrexate/pharmacokinetics , Models, Biological , Rats , Rats, Wistar
11.
Gen Pharmacol ; 33(4): 341-6, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10523073

ABSTRACT

The antimetabolites 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of children's acute lymphoblastic leukemia (ALL). The biochemical mechanisms underlying the increased therapeutic efficacy of the combination of these drugs have not yet been elucidated. However, both drugs interact with important pathways. such as purine de novo synthesis (PDNS), purine salvage, and methylation reactions. A review of the mechanistic aspects of the interactions between 6-MP and MTX is given.


Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Mercaptopurine/pharmacokinetics , Methotrexate/pharmacokinetics , Antimetabolites, Antineoplastic/metabolism , Antimetabolites, Antineoplastic/therapeutic use , Child , Drug Interactions , Humans , Mercaptopurine/metabolism , Mercaptopurine/therapeutic use , Methotrexate/metabolism , Methotrexate/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
12.
Tidsskr Nor Laegeforen ; 119(9): 1334-5, 1999 Apr 10.
Article in Norwegian | MEDLINE | ID: mdl-10327859
13.
Biochem Pharmacol ; 57(9): 1067-72, 1999 May 01.
Article in English | MEDLINE | ID: mdl-10796077

ABSTRACT

The glycolethers 2-methoxyethanol (2-ME), 2-ethoxyethanol (2-EE), and 2-butoxyethanol are widely used organic solvents with teratogenic, spermatotoxic, and hematotoxic effects due to the respective alkoxyacetic acid metabolites formed via alcohol dehydrogenase (ADH). ADH displays sexually dimorphic activities in adult rats, and is probably at least in part under the control of testosterone. The aim of this study was to investigate whether induction of ADH is also sex-dependent. Ethanol, 2-ME, and 2-EE were tested as inducers of hepatic and gastric ADH in female, male, and castrated male rats. The activity of hepatic ADH was higher in female than in male rats, while the activity of gastric ADH was higher in male than in female rats. The activities of ADH increased with increasing chain length of the glycolethers and alcohols. Castration of male rats led to a female pattern of ADH activity, i.e. increased activity of hepatic ADH and decreased activity of gastric ADH. Ethanol had no inducing effect on hepatic ADH in either male or female rats. 2-ME and 2-EE caused an increase in the activity of hepatic ADH in male and castrated male rats only. The present data demonstrate a different expression of ADH isoenzymes in male and female rats, and a sex-dependent induction of ADH isoenzymes. The different possible regulatory mechanisms for the different ADH isoenzymes require further investigation.


Subject(s)
Alcohol Dehydrogenase/biosynthesis , Sex Characteristics , Animals , Body Weight/drug effects , Enzyme Induction/drug effects , Ethanol/pharmacology , Ethylene Glycols/pharmacology , Female , Liver/drug effects , Liver/enzymology , Male , Orchiectomy , Rats , Stomach/drug effects , Stomach/enzymology
14.
Toxicol Appl Pharmacol ; 150(1): 86-90, 1998 May.
Article in English | MEDLINE | ID: mdl-9630456

ABSTRACT

The glycolethers 2-methoxyethanol (2-ME), 2-ethoxyethanol (2-EE), and 2-butoxyethanol (2-BE) are used as solvents and have teratogenic, spermatotoxic, and hematotoxic effects. These glycolethers are oxidized to their corresponding alkoxyacetic acids, probably by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). This metabolic conversion of the glycolethers is a prerequisite for development of toxicity, as the toxic effects have been shown to be due to the alkoxyacetic acid metabolites. Three isoenzymes of ADH have been detected in rat tissues. The liver contains two of these isoenzymes, ADH-2 and ADH-3. It has also been shown that the activity level of ADH is strongly sex dependent, with higher activity in females than in males. In the present study, we have investigated whether one or both of the ADH isoenzymes in male and female rat livers were able to oxidize 2-ME, 2-EE, and 2-BE and whether one or both of the ADH isoenzymes in male rat liver were able to oxidize 2-pentyloxyethanol and 2-hexyloxyethanol. Our results indicated that only the ADH-3 isoenzyme effectively oxidized the glycolethers in rat liver. Both ADH-2 and ADH-3 were able to oxidize medium chain aliphatic alcohols with a chain length corresponding to the glycolethers. The activity of ADH is higher in female than in male rat liver. However, it was the same ADH isoenzyme (ADH-3) that oxidized the different glycolethers tested in both male and female rat livers, and the substrate specificity was 2-BE > 2-EE > 2-ME.


Subject(s)
Alcohol Dehydrogenase/metabolism , Ethylene Glycols/metabolism , Isoenzymes/metabolism , Liver/enzymology , Animals , Electrophoresis, Starch Gel , Female , Horses , Kinetics , Male , Oxidation-Reduction , Rats , Rats, Wistar , Sex Characteristics , Substrate Specificity
15.
Biochem Pharmacol ; 55(10): 1641-6, 1998 May 15.
Article in English | MEDLINE | ID: mdl-9634000

ABSTRACT

The effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism was studied in four human leukemic cell lines in vitro. CCRF-CEM, WI-L2, TBJ, and HL-60 all expressed thiopurine methyltransferase (TPMT) activity. The cells were grown in horse serum-supplemented RPMI 1640 medium to which was added 4 microM of 6-MP or 4 microM of 6-MP and 20 nM of MTX. The presence of MTX resulted in a 2.1-, 1.7-, 2.4- and 8-fold increase in the concentrations of methylmercaptopurine ribonucleotides (MMPRP) in CEM, WI-L2, TBJ, and HL-60 cells, respectively (P < 0.0008). The concentrations of 6-thioguanine nucleotides (6 TGN) increased 1.9-, 1.4-, 2.4- and 1.9-fold in the same cell lines (P < 0.02). The four cell lines differed with respect to the effect of MTX on the consumption of 6-MP from the medium; CEM consumed more 6-MP and WI-L2 less 6-MP from media containing MTX than from media containing 6-MP only (P = 0.005 and 0.02, respectively). MTX did not affect the consumption of 6-MP by TBJ cells (P = 0.17). Media in which HL-60 cells had been grown did not contain detectable amounts of 6-MP at the end of the experiment. The simultaneous increase in methylated 6-MP metabolites and 6-TGN represents a possible explanation for the synergism of MTX and 6-MP; however, the clinical importance of increased MMPRP remains to be elucidated.


Subject(s)
Guanine Nucleotides/metabolism , Mercaptopurine/metabolism , Methotrexate/pharmacology , Thioguanine/chemistry , Culture Media , Guanine Nucleotides/chemistry , Humans , Methylation , Tumor Cells, Cultured
16.
Biochim Biophys Acta ; 1395(3): 345-60, 1998 Feb 11.
Article in English | MEDLINE | ID: mdl-9512670

ABSTRACT

Expression of the c-fos proto-oncogene is induced by numerous stimuli some of which are transmitted through the Ras/Raf/MAP kinase or the cAMP-dependent protein kinase (PKA) pathways. The effect of cell-specific interactions between these pathways on c-fos expression was investigated by exposing quiescent NIH3T3 cells to serum, forskolin, or a combination. Co-stimulation with serum and forskolin resulted in a more than additive increase in c-fos transcription. Synergistic increase in c-fos promoter activity was also observed in transient transfection studies after co-stimulation with serum plus forskolin or co-transfection with c-Raf and PKA expression plasmids. Analysis of the cAMP signaling pathway revealed that the synergy was neither due to an increase in PKA activity nor to Ser-133 phosphorylation/activation of CREB. The activation status of the MAP kinases ERK1 and ERK2 in co-treated cells was comparable to that in serum-treated cells. Co-stimulation with forskolin did not alter the phosphorylation state of Elk-1 compared to serum-induced phosphorylation of Elk-1. Deletion of c-fos promoter elements previously shown to be important for regulation of c-fos expression in response to mitogens indicates a role for SRE and FAP-1 elements.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , DNA-Binding Proteins/metabolism , Genes, fos , Mitogen-Activated Protein Kinases , Proto-Oncogene Proteins c-fos/biosynthesis , Proto-Oncogene Proteins c-raf/metabolism , Signal Transduction , ras Proteins/metabolism , 3T3 Cells , Animals , Base Sequence , Chloramphenicol O-Acetyltransferase/biosynthesis , Colforsin/pharmacology , Cyclic AMP/metabolism , Cyclic AMP Response Element-Binding Protein/metabolism , DNA Primers , Kinetics , Mice , Mitogen-Activated Protein Kinase 1 , Mitogen-Activated Protein Kinase 3 , Molecular Sequence Data , Polymerase Chain Reaction , Promoter Regions, Genetic , Recombinant Fusion Proteins/biosynthesis , Transcription Factor AP-1/metabolism , Transcription, Genetic/drug effects , Transfection
17.
Pharmacol Toxicol ; 81(5): 199-204, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9396083

ABSTRACT

The effect of the transmethylation inhibitor 3-deazaadenosine on transcription levels of genes associated with apoptosis was investigated in HL-60 cells. After incubation of HL-60 cells with 100 microM 3-deazaadenosine for 45 min., a schedule known to perturb transmethylation metabolites and initiate apoptosis in these cells, a 50% decrease in c-myc and a 50% increase in bcl-2 RNA steady-state levels compared to control cells were observed. Transcription levels of c-myc continued to decrease after extended exposure to 3-deazaadenosine, while bcl-2 mRNA levels dropped to 25% and 30% below those in control cells after 1.5 hr and 3 hr, respectively. The expression levels of the bcl-2 related bax gene, showed a similar pattern as bcl-2; a 60% increase was initially measured, but after 1.5 and 3 hr, bax transcripts were 80% and 70% respectively, of those found in untreated cells. Another bcl-2 related gene, bcl-x, was previously reported to generate two transcripts in human cells. The long variant bcl-x1 acts as bcl-2, while the short form bcl-xs induces apoptosis. We were unable to detect bcl-xs transcripts in untreated and 3-deazaadenosine treated cells by the highly sensitive reverse transcriptase polymerase chain reaction method. This suggests that this gene product may not be involved in 3-deazaadenosine induced apoptosis in HL-60 cells. Bcl-x1 mRNA levels, however, slowly decreased with about 50% after 1.5 or 3 hr 3-deazaadenosine treatment. It is concluded that 3-deazaadenosine initiated apoptosis affects c-myc, bcl-2, bax and bcl-x1 mRNA levels.


Subject(s)
Apoptosis/genetics , Gene Expression/drug effects , Genes, bcl-2/drug effects , Genes, myc/drug effects , Proto-Oncogene Proteins c-bcl-2 , Tubercidin/pharmacology , HL-60 Cells/drug effects , HL-60 Cells/metabolism , Humans , Proto-Oncogene Proteins/genetics , RNA, Messenger , bcl-2-Associated X Protein
18.
Clin Pharmacol Ther ; 62(1): 60-73, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9246020

ABSTRACT

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT activity is regulated by a common genetic polymorphism that is associated with large individual variations in thiopurine toxicity and efficacy. We previously cloned the functional gene for human TPMT and reported a common variant allele for low enzyme activity, TPMT*3A, that contains point mutations at cDNA nucleotides 460 and 719. In the present study, we set out to determine the number, types, and frequencies of TPMT variant alleles associated with low enzyme activity in clinical laboratory samples in the United States and to compare those results with data obtained from two different ethnic groups. We identified a total of six different variant alleles for low TPMT activity in the 283 clinical laboratory samples studied. The most common variant was *3A; the second most frequent variant allele, *3C, contained only the nucleotide 719 polymorphism; and four other variant alleles were detected. TPMT*3A also appeared to be the most common variant allele in a Norwegian white population sample, but it was not found in a population sample of Korean children. However, *3C was present in samples from the Korean children, as was novel allele, *6. Characterization of variant alleles for low TPMT enzyme activity will help make it possible to assess the potential clinical utility of deoxyribonucleic acid-based diagnostic tests for determining TPMT genotype.


Subject(s)
Erythrocytes/enzymology , Methyltransferases/genetics , Alleles , Asian People/genetics , DNA Primers , Humans , Korea , Norway , Polymorphism, Genetic , United States , White People/genetics
19.
Ther Drug Monit ; 19(3): 318-26, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9200774

ABSTRACT

The objectives of this study were to establish monitoring of azathioprine (AZA) treatment in renal allograft recipients by red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) measurements and to characterize the variability of RBC thiopurine methyltransferase (TPMT) activity and the effects on 6-TGN levels and the incidence of rejection episodes. In 82 renal allograft recipients, the effect of standard AZA dosage (3 mg/kg tapered to 1 mg/kg) was compared with higher dosages (3 mg/kg for several days) under 6-TGN monitoring. The authors measured TPMT in these patients and in a group not receiving AZA. The authors did not find an inverse correlation between RBC TPMT activity and 6-TGN concentrations, and baseline TPMT activity did not predict the incidence of rejection episodes The slight increase in RBC TPMT activity after transplant was associated with the use of furosemide rather than AZA; in the five patients receiving furosemide for less than 10 days, TPMT activity declined. The higher AZA dosage in the 6-TGN monitored group was not sufficient to increase RBC 6-TGN to target levels (100 to 200 pmol/8 x 10(8) RBC); median 6-TGN levels were similar in the two groups, as was the incidence of rejection episodes. Based on these findings, the authors suggest that higher dosages be studied in conjunction with 6-TGN monitoring, to explore the possibilities for therapeutic improvements.


Subject(s)
Azathioprine/blood , Drug Monitoring , Erythrocytes/metabolism , Guanine Nucleotides/blood , Immunosuppressive Agents/blood , Kidney Transplantation , Methyltransferases/blood , Thionucleotides/blood , Adolescent , Adult , Aged , Erythrocytes/enzymology , Female , Humans , Male , Middle Aged
20.
Cancer Chemother Pharmacol ; 40(4): 367-70, 1997.
Article in English | MEDLINE | ID: mdl-9225958

ABSTRACT

PURPOSE: To elucidate the effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism in rats. METHODS: Fourteen rats were given 6-MP 20 mg/kg daily for 7 days. Seven of the rats were also given MTX 20 mg/kg on days 5 and 7. Blood samples were obtained from all rats on days 0.5 and 8, and red blood cell (RBC) lysates were analysed for thiopurine methyltransferase (TPMT) activity and the concentration of methylated 6-MP metabolites [methyl mercaptopurine ribonucleotides (MMPRP)] and 6-thioguanine nucleotides (6-TGN). RESULTS: The concentration of MMPRP increased 2.4 times from day 5 to day 8 in RBCs from rats given MTX in addition to 6-MP, as against 1.2 times in rats given 6-MP alone (P = 0.003). 6-TGN levels increased and TPMT activity decreased from day 5 to day 8, with no difference between the 6-MP and the 6-MP plus MTX groups. CONCLUSIONS: Single bolus doses of MTX increase the concentration of MMPRP in rats given daily s.c. doses of 6-MP, with no effect on 6-TGN concentration or TPMT activity.


Subject(s)
Erythrocytes/metabolism , Mercaptopurine/metabolism , Methotrexate/pharmacology , Nucleic Acid Synthesis Inhibitors/pharmacology , Animals , Erythrocytes/drug effects , Guanine Nucleotides/analysis , Guanine Nucleotides/metabolism , Male , Mercaptopurine/pharmacology , Methylthioinosine/analysis , Methylthioinosine/metabolism , Methyltransferases/metabolism , Rats , Rats, Wistar , Thionucleotides/analysis , Thionucleotides/metabolism
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