PMID- 15228169
OWN - NLM
STAT- MEDLINE
DCOM- 20040728
LR  - 20190906
IS  - 0163-4356 (Print)
IS  - 0163-4356 (Linking)
VI  - 26
IP  - 2
DP  - 2004 Apr
TI  - Analytic aspects of monitoring therapy with thiopurine medications.
PG  - 220-6
AB  - The thiopurine medications 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), and 
      azathioprine are used in treatment of childhood acute lymphoblastic leukemia, 
      autoimmune diseases, and, in the case of azathioprine, in solid organ 
      transplantation. They are converted in vivo to the active 6-thioguanine 
      nucleotides (6-TGN). One person in 300 in white populations has low or 
      undetectable TPMT activity and is at risk for accumulating 6-TGN with the 
      consequence of severe, life-threatening myelosuppression. A rational therapeutic 
      strategy for thiopurine drug use is to first determine TPMT phenotype/genotype 
      and then to adjust the dosage on an individual basis. Determination of 
      erythrocyte 6-TGN levels can further help to optimize therapy. TPMT activity 
      (phenotype) is determined in erythrocytes using radiochemical or HPLC procedures. 
      Recent HPLC procedures show good agreement with the original radiochemical 
      method, while offering simplified sample pretreatment and improved precision. To 
      date, 12 mutant alleles responsible for TPMT deficiency have been published. 
      Restriction fragment length polymorphism PCR and allele-specific PCR have been 
      used for detection of TPMT mutations. Genotyping methods that allow a higher 
      throughput include real-time PCR (LightCycler) and denaturing HPLC. Numerous HPLC 
      methods have been reported for quantification of 6-TGN. The majority involve acid 
      hydrolysis to 6-TG at high temperature. There are substantial differences in the 
      hydrolysis step, extraction procedure, chromatographic conditions and method of 
      detection. Erythrocyte 6-TGN concentrations can vary up to 2.6-fold depending on 
      the HPLC method. The method that has found the greatest application in clinical 
      studies is that of Lennard. This has served as the basis for the establishment of 
      treatment-related therapeutic ranges for thiopurine therapy. These ranges will 
      not necessarily be applicable when other methodology is used. There is an urgent 
      need to harmonize the analytic procedures for 6-TGN.
FAU - Armstrong, Victor W
AU  - Armstrong VW
AD  - Department of Clinical Chemistry, George-August University, D-37075 Goettingen, 
      Germany. varmstro@med.uni-goettingen.de
FAU - Shipkova, Maria
AU  - Shipkova M
FAU - von Ahsen, Nicolas
AU  - von Ahsen N
FAU - Oellerich, Michael
AU  - Oellerich M
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Ther Drug Monit
JT  - Therapeutic drug monitoring
JID - 7909660
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Purines)
RN  - E7WED276I5 (Mercaptopurine)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (thiopurine methyltransferase)
RN  - FTK8U1GZNX (Thioguanine)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Antimetabolites, Antineoplastic/administration & 
      dosage/pharmacokinetics/therapeutic use
MH  - Azathioprine/administration & dosage/pharmacokinetics/therapeutic use
MH  - Drug Monitoring/*methods
MH  - Genotype
MH  - Humans
MH  - Immunosuppressive Agents/administration & dosage/pharmacokinetics/therapeutic use
MH  - Mercaptopurine/administration & dosage/pharmacokinetics/therapeutic use
MH  - Methyltransferases/genetics/metabolism
MH  - Phenotype
MH  - Purines/administration & dosage/*pharmacokinetics/therapeutic use
MH  - Thioguanine/administration & dosage/pharmacokinetics/therapeutic use
RF  - 53
EDAT- 2004/07/02 05:00
MHDA- 2004/07/29 05:00
CRDT- 2004/07/02 05:00
PHST- 2004/07/02 05:00 [pubmed]
PHST- 2004/07/29 05:00 [medline]
PHST- 2004/07/02 05:00 [entrez]
AID - 10.1097/00007691-200404000-00024 [doi]
PST - ppublish
SO  - Ther Drug Monit. 2004 Apr;26(2):220-6. doi: 10.1097/00007691-200404000-00024.