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Mechanism Of Action
Mercaptopurine activation occurs via hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) and several enzymes to form 6-thioguanine nucleotides (6-TGNs). Incorporation of 6-TGN into nucleic acids (instead of purine bases) results in cell-cycle arrest and cell death. Mercaptopurine competes with hypoxanthine and guanine for HGPRTase and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).
The relative bioavailability of PURIXAN was compared to mercaptopurine 50 mg tablets in 62 healthy subjects in a single-dose, two-period, crossover study under fasting conditions. Bioequivalence was demonstrated based on the primary PK parameters AUC(0-t) and AUC(0-∞). Cmax did not demonstrate bioequivalence. The mean Cmax following PURIXAN administration was 34% higher than the tablet.
Absorption and Bioavailability
Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown.
Following a single 50 mg dose of PURIXAN under fasting conditions the median (range) AUC was 136 h*ng/mL (74.2-264.8 h*ng/mL) and Cmax was 95 ng/mL (39.5-204 ng/mL).
The volume of distribution usually exceeded that of the total body water. There is negligible entry of mercaptopurine into cerebrospinal fluid.
Mercaptopurine is inactivated via two major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-mercaptopurine. The second inactivation pathway is oxidation, which is catalyzed by xanthine oxidase. The product of oxidation is the inactive metabolite 6-thiouric acid.
Following administration of PURIXAN, the elimination half-life (t&fract12;) was approximately 2 hours.
After oral administration of 35S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. In one subject, a total of 46% of the dose could be accounted for in the urine (as parent drug and metabolites) in the first 24 hours.
TPMT enzyme activity is highly variable in patients because of a genetic polymorphism in the TPMT gene. For Caucasians and African Americans, approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable TMPT activity. Approximately 10% of patients have one TPMT nonfunctional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of patients have normal TPMT activity with two functional alleles.
Homozygous-deficient patients with little or no detectable TPMT activity, if given usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs predisposing them to mercaptopurine toxicity. Heterozygous patients with low or intermediate TPMT activity accumulate higher concentrations of active 6-TGNs than patients with normal TPMT activity and are more likely to experience mercaptopurine toxicity [see WARNINGS AND PRECAUTIONS].
TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity.
Genotypic and phenotypic testing of TPMT status are available. Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT*2, TPMT*3A and TPMT*3C— account for about 95% of individuals with reduced levels of TPMT activity. Individuals homozygous for these alleles are TPMT deficient and those heterozygous for these alleles have variable TPMT (low or intermediate) activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and can also be informative. Caution must be used with phenotyping since some coadministered drugs can influence measurement of TPMT activity in blood, and recent blood transfusions will misrepresent a patient's actual TPMT activity.
The safety and effectiveness of mercaptopurine for the treatment of ALL in pediatric and adult patients have not been established in adequate and well-controlled trials [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 5/9/2014
This monograph has been modified to include the generic and brand name in many instances.
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