MERCAPTOPURINE ANHYDROUS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C5H4N4S
Molecular Weight	152.177
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

S=C1NC=NC2=C1N=CN2

InChI

InChIKey=GLVAUDGFNGKCSF-UHFFFAOYSA-N

InChI=1S/C5H4N4S/c10-5-3-4(7-1-6-3)8-2-9-5/h1-2H,(H2,6,7,8,9,10)

HIDE SMILES / InChI

Molecular Formula	C5H4N4S
Molecular Weight	152.177
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Mercaptopurine, marketed under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Mercaptopurine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (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). PURINETHOL (mercaptopurine) is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia as part of a combination regimen. The response to this agent depends upon the particular subclassification of acute lymphatic leukemia and the age of the patient (pediatric or adult).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Amidophosphoribosyltransferase 3	Inhibitor 8,297
DNA 278	Inhibitor 8,297
prostaglandin biosynthetic process 23	Inhibitor 8,297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute lymphoblastic leukemia 27	Primary		Approved 8,429	PURINETHOL

C_max

Value	Dose	Co-administered	Analyte	Population
74 ng/mL	75 mg/m² single, intravenous		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens
69.5 ng/mL	600 mg single, oral		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
200 ng × h/mL	75 mg/m² single, intravenous		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens
135.8 ng × h/mL	600 mg single, oral		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
2 h	75 mg/m² single, intravenous		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
81%			MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
100 mg 3 times / day multiple, oral Studied dose	unhealthy, 37 years	Other AEs: Anorexia, Nausea...
50 mg/m2/hour 1 times / 2 days multiple, intravenous Studied dose	unhealthy, Median age 9.5 years	Other AEs: ALT increased, AST increased...
1125 mg/m2 1 times / day multiple, intravenous Studied dose	unhealthy, age range 2 to 17 years	Other AEs: Pancytopenia, Neutropenic fever...
1250 mg/m2 1 times / day multiple, intravenous Highest studied dose	unhealthy, age range 4 to 14 years
50 mg/m2/hour 1 times / 3 weeks multiple, intravenous Studied dose	unhealthy, median age 10 years	DLT: Mucositis...

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AEs

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AE	Dose	Population
Anorexia	100 mg 3 times / day multiple, oral Studied dose	unhealthy, 37 years
Hepatic disease	100 mg 3 times / day multiple, oral Studied dose	unhealthy, 37 years
Myelosuppression	100 mg 3 times / day multiple, oral Studied dose	unhealthy, 37 years
Nausea	100 mg 3 times / day multiple, oral Studied dose	unhealthy, 37 years
Vomiting	100 mg 3 times / day multiple, oral Studied dose	unhealthy, 37 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587	inhibitor 1,767	inhibitor 1,852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP1B3 706 OATP1B1 788 BSEP 402 MRP4 204 MRP3 157 CYP2C19 1,478 CYP1A2 1,524	TPMT 5

Drug as perpetrator

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Target	Modality	Activity
BSEP 403	inhibitor 3,277	no [IC50 133 uM]
CYP1A2 1,692	inhibitor 3,277	no
CYP2C19 1,553	inhibitor 3,277	no
CYP2C9 1,819	inhibitor 3,277	no
CYP2D6 1,891	inhibitor 3,277	no

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
TPMT 5	substrate 3,367	yes

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY556883	https://www.001chemical.com/chem/50-44-2
3B Scientific (Wuhan) Corp	3B3-010771	http://www.3bsc.com/index/pro_info.php?id=33264
AA Blocks	AA0038MP	http://www.aablocks.com/goods/Goods/detail?id=AA0038MP
Aaron Chemicals	AR0039EH	http://www.aaronchem.com/50-44-2
abcr GmbH	AB310793	http://www.abcr.com/shop/en/AB310793

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PubMed

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Title	Date	PubMed
Veno-occlusive disease of the liver associated with thiopurines in a child with acute lymphoblastic leukemia.	2000 Jul-Aug	10914056
Pharmacokinetic considerations in the treatment of inflammatory bowel disease.	2001	11707060
Genotype-phenotype correlation for thiopurine S-methyltransferase in healthy Italian subjects.	2001 Apr	11372592
Hepatic dysfunction in children with acute lymphoblastic leukemia in remission: relation to hepatitis infection.	2001 Apr	11260570
Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine.	2001 Apr 15	11304783

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Patents

Sample Use Guides

In Vivo Use Guide

Usual Adult Dose for Intestinal Arterial Insufficiency Initial Dosage: Oral: 2.5 mg/kg of body weight per day (100 to 200 mg in the average adult). This dose may be continued daily for several weeks or more in some patients. If, after 4 weeks at this dosage, there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased up to 5 mg/kg daily. A dosage of 2.5 mg/kg per day may result in a rapid fall in leukocyte count within 1 to 2 weeks in some adults with acute lymphatic leukemia and high total leukocyte counts. The total daily dosage may be given at one time. It is calculated to the nearest multiple of 25 mg. Maintenance Therapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. A usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg per day as a single dose. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia. Usual Adult Dose for Acute Lymphoblastic Leukemia Initial Dosage: Oral: 2.5 mg/kg of body weight per day (100 to 200 mg in the average adult). This dose may be continued daily for several weeks or more in some patients. If, after 4 weeks at this dosage, there is no clinical improvement and no definite evidence of leukocyte or platelet depression, the dosage may be increased up to 5 mg/kg daily. A dosage of 2.5 mg/kg per day may result in a rapid fall in leukocyte count within 1 to 2 weeks in some adults with acute lymphatic leukemia and high total leukocyte counts. The total daily dosage may be given at one time. It is calculated to the nearest multiple of 25 mg. Maintenance Therapy: Once a complete hematologic remission is obtained, maintenance therapy is considered essential. A usual daily maintenance dose of mercaptopurine is 1.5 to 2.5 mg/kg per day as a single dose. Mercaptopurine should rarely be relied upon as a single agent for the maintenance of remissions induced in acute leukemia. Usual Adult Dose for Crohn's Disease - Acute Oral: 1.0 to 1.5 mg/kg of body weight per day Usual Adult Dose for Crohn's Disease - Maintenance Oral: 1.0 to 1.5 mg/kg of body weight per day Usual Adult Dose for Ulcerative Colitis - Maintenance Oral: 1.0 to 1.5 mg/kg of body weight per day Usual Adult Dose for Inflammatory Bowel Disease Oral: 1.0 to 1.5 mg/kg of body weight per day

Route of Administration: Oral

In Vitro Use Guide

Mercaptopurine (10-500 ug/ml) inhibits in a dose-dependent manner the production of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 by unseparated spleen cells as well as that of 6-keto-PGF1 alpha by adherent peritoneal macrophages.