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

Chrzanowska, Maria; Kołecki, P; Duczmal-Cichocka, Barbara; J, Fiet

doi:10.1016/s0928-0987(99)00027-5

Cited by 31 publications

(46 citation statements)

References 24 publications

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“…[2] but contradicting with Chrzanowska et al [24] who found no relation, although theoretically the 2 metabolites should be negatively correlated, being part of competing pathways (Figure 1). A possible explanation could be that the majority of the recruited children have wild type TPMT genotype, yielding proportional amounts of both metabolites in a dose dependent manner.…”

Section: Analysis Of Patient Samplesmentioning

confidence: 81%

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

Abdelsayed¹,

A²,

Sidhom³

et al. 2017

J Anal Bioanal Tech

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The need of a robust, sensitive HPLC method for the quantitation of 6-thioguaninenucleotides (6-TG) and 6-methylmercaptopurine (6-MMP) is indispensable to relate levels of these metabolites with emergence of signs of toxicity in patients undergoing treatment with 6-mercaptopurine (6-MP), paving the road to accurate dose calculations and thus providing a cost-effective treatment approach. Previously reported methods were either laborious, required special types of C18 columns, or had long run times. A Design of Experiments (DoE) approach targeting the shortest run time with greatest selectivity was adopted using a user friendly HPLC method development simulation software (DryLab®). Analytes eluted within 10 min, at 3.8, 4.2, 5.6 and 7.5 min for 6-TG, 6-MP, 6-MMP and Dithiothreitol (DTT) respectively. Excellent recovery percentages of 90.9 ± 14.4, 87.8 ± 6.7 and 92.1 ± 9.08, respectively were obtained. The method proved its validity and robustness according to the International Conference on Harmonization (ICH) guidelines. The LOD of 6-MP, 6-TG and 6-MMP were 6, 9 and 24 pmol/8 × 108 RBCs, respectively. Twenty-Two Acute Lymphocytic Leukemia (ALL) children recruited from 57357 Cancer Hospital (Cairo, Egypt) had their 6-MP metabolites measured using the developed method. A strong negative correlation was manifested between TG and RBCs count and hemoglobin (p=0.009 and 0.002 respectively). WBC and neutrophils showed a negative correlation to TG at Continuation 1 phase of treatment, confirming the association of TG with myelotoxicity. The significant correlation between MMP and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (p=0.030, 0.004) explained its potential hepatotoxicity.

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Section: Analysis Of Patient Samplesmentioning

confidence: 81%

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

Abdelsayed¹,

A²,

Sidhom³

et al. 2017

J Anal Bioanal Tech

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“…The outcome of the model validation using data obtained from Chrzanowska et al . is shown in Figure . The data in this figure represent individual measured concentrations from the children.…”

Section: Resultsmentioning

confidence: 99%

“…Median profiles (continuous lines), 95% prediction intervals (broken lines) and observed data (filled circles) for intracellular RBC 6‐TGN and 6‐MMPR following oral dosing of 6‐MP (50 mg m –2 daily) in ALL children for at least 1 month …”

Section: Resultsmentioning

confidence: 99%

Physiologically based pharmacokinetic model for 6‐mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity

Ogungbenro

Aarons

2015

Brit J Clinical Pharma

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AIMSTo extend the physiologically based pharmacokinetic (PBPK) model developed for 6-mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6-mercaptopurine. METHODSThe developed PBPK model was extended for 6-mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6-mercaptopurine and its metabolites. Age-dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data. RESULTSThe model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6-thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild-type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses. CONCLUSIONSThe developed PBPK model has been extended for 6-mercaptopurine and can be used to predict plasma 6-mercaptopurine and tissue concentration of 6-mercaptopurine, 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6-mercaptopurine dosing, achieve better clinical outcome and reduce toxicity. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 6-mercaptopurine is an antimetabolite prodrug used in the treatment of cancers and inflammatory diseases. It has a narrow therapeutic index with potential life-threatening toxicity linked to its active metabolite, 6-thioguanine nucleotide.• A physiologically based pharmacokinetic (PBPK) model has been developed for 6-mercaptopurine in adults and children.• TPMT, an enzyme responsible for the intracellular metabolism of 6-mercaptopurine has been shown to have three genetic polymorphic groups; high (homozygous wild-type), intermediate (heterozygous variant) and low (homozygous variant) activity groups. WHAT THIS STUDY ADDS• The developed PBPK model has been extended to account for intracellular metabolism of 6-mercaptopurine incorporating genetic polymorphism in TPMT activity.• The model can be used to predict plasma and tissue concentrations of 6-mercaptopurine and its metabolites, including 6-thioguanine nucleotide which is responsible for activity and toxicity.

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“…Verschiedene Gruppen konnten bei Patienten mit ALL [35,36] oder nach Organtransplantation [13,14,37] eine Assoziation zwischen den 6-TGN-Konzentrationen in Erythrozyten und dem Risiko einer Leukopenie beobachten. Verschiedene Gruppen konnten bei Patienten mit ALL [35,36] oder nach Organtransplantation [13,14,37] eine Assoziation zwischen den 6-TGN-Konzentrationen in Erythrozyten und dem Risiko einer Leukopenie beobachten.…”

Section: Die Variabilita èT Der Pharmakokinetik Von Thiopurinmedikameunclassified

Therapie mit Thiopurin-Medikamenten TDM – und Pharmakogenomik der TPMT/Therapy with Thiopurine Drugs – TDM and Pharmacogenomics of TPMT

Shipkova¹,

Ahsen²

2003

LaboratoriumsMedizin

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Zusammenfassung: Bei den Thiopurinen gibt es eine u Èber Jahrzehnte gewachsene klinische Erfahrung in der Therapie von Leuka Èmien und der Immunsuppression. Bereits seit u Èber 20 Jahren ist ein genetischer Polymorphismus der TPMT (Thiopurin-S-Methyltransferase) bekannt, des Schlu Èsselenzyms der Thiopurinentgiftung. Eine komplette TPMT-Defizienz fu Èhrt zu einer hohen Konzentration aktiver Metabolite unter einer Standardtherapie mit Thiopurinen, wodurch eine lebensbedrohliche Myelosuppression ausgelo Èst wird. Eine Pha Ènotypisierung durch Messung der TPMT-Aktivita Èt in Erythrozyten vor Beginn einer Thiopurintherapie wird dringend empfohlen, da hierdurch die meisten Risikopatienten identifiziert werden ko Ènnen. Die Pha Ènotypisierung kann mittels eines radiochemischen oder HPLC-basierten Assays durchgefu Èhrt werden. Bei einer Bluttransfusion innerhalb der letzten 2±3 Monate ist eine Genotypisierung die Methode der Wahl. Allerdings besteht bei der Genotypisierung ein geringes Restrisiko bzgl. der Pra Èdiktion einer TPMT-Defizienz, da routinema Èûig nur auf Vorliegen der ha Èufigsten Defektmutationen untersucht werden kann. Auf Grund der sehr groûen interindividuellen Variation der Thiopurinpharmakokinetik wird zur weiteren Optimierung einer Therapie die Bestimmung der 6-Thioguaninnukleotid-Konzentration in Erythrozyten empfohlen. Durch Messung dieser aktiven Thiopurinmetabolite ermo Èglicht auch eine U È berpru Èfung der Patientencompliance. Das Drug-Monitoring kann nicht die Kontrolle allgemeiner Toxizita Ètsparameter (Leukozytenzahl, Transaminasen usw.) ersetzen, es liefert vielmehr erga Ènzende Information. Diese Vorgehensweise ermo Èglicht eine relativ sichere, effektive und nebenwirkungsarme Therapie mit Thiopurinmedikamenten.Schlu È sselwo È rter: Thiopurine; Thiopurin S-Methyltransferase; Drug-Monitoring; Genotyp; Pha Ènotyp.Summary: Clinicians look back on decades of experience with the use of thiopurine drugs in the treatment of leukaemia and immunosuppression. TPMT (thiopurine-S-methyltransferase) is the key enzyme of thiopurine drug catabolism. The enzyme activity underlies a genetic polymorphism that has been known for over 20 years. TPMT deficiency leads to accumulation of active metabolites and life-threatening myelosuppression under therapy with standard dosage. Phenotyping by measuring the erythrocyte TPMT activity before initiation of any thiopurine drug therapy is highly recommended to detect TPMT-deficient patients. Phenotyping methods include a radiochemical assay and HPLC-based methods. A blood transfusion within the last 2±3 months may cause false test results due to contamination with donor erythrocytes. In such cases, genotyping is superior. A low risk of not detecting all deficient cases exists, since routine screening can normally only check for the presence of the most common deficiency-causing alleles. Individual thiopurine pharmacokinetics are variable and therapeutic drug monitoring is recommended for therapy optimization and compliance check. Therapeutic drug monitoring is no sub...

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

Cited by 31 publications

References 24 publications

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

HPLC Determination of the Levels of 6-Mercaptopurine Metabolites Suitable for the Clinical Risk Assessment of its Toxicity among Egyptian Children with Acute Lymphocytic Leukemia

Physiologically based pharmacokinetic model for 6‐mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity

Therapie mit Thiopurin-Medikamenten TDM – und Pharmakogenomik der TPMT/Therapy with Thiopurine Drugs – TDM and Pharmacogenomics of TPMT

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