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Volume 118, Issue 4, Pages (April 2000)

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1 Volume 118, Issue 4, Pages 705-713 (April 2000)
Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease  Marla C. Dubinsky, Stéphanie Lamothe, Hui Ying Yang, Stephan R. Targan, Daniel Sinnett, Yves Théorêt, Ernest G. Seidman  Gastroenterology  Volume 118, Issue 4, Pages (April 2000) DOI: /S (00) Copyright © 2000 American Gastroenterological Association Terms and Conditions

2 Fig. 1 6-MP metabolism. Oral AZA is rapidly converted to 6-MP by a nonenzymatic process.19 Initial 6-MP transformations occur along competing catabolic (XO, xanthine oxidase; TPMT) and anabolic (HPRT, hypoxanthine phosphoribosyltransferase) enzymatic pathways. Once formed, 6-TImP may be transformed into 6-TGN by the rate-limiting inosine monophosphate dehydrogenase (IMPDH) or methylated into 6-MMPR. Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

3 Fig. 2 Correlation of quartile 6-MP metabolite levels with clinical response in IBD. (A) The frequency of clinical response was significantly higher within the upper 6-TG level quartiles (>235 pmol/8 × 108 RBC). *P < (B) Association between 6-MMP quartile levels and clinical response. No significant differences were observed (P = 0.48). n, number of clinical evaluation points per quartile. Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

4 Fig. 2 Correlation of quartile 6-MP metabolite levels with clinical response in IBD. (A) The frequency of clinical response was significantly higher within the upper 6-TG level quartiles (>235 pmol/8 × 108 RBC). *P < (B) Association between 6-MMP quartile levels and clinical response. No significant differences were observed (P = 0.48). n, number of clinical evaluation points per quartile. Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

5 Fig. 3 Frequency of 6-TG levels > 235 (pmol/8 × 108 RBC) at clinical evaluation points corresponding to therapeutic response, compared with points of therapeutic failure. *P < Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

6 Fig. 4 Relationship between 6-MP dose and clinical response in IBD. No significant differences were observed in the frequency of clinical response within 6-MP dose quartiles. AZA dose was converted to 6-MP dose by a factor of n, number of clinical evaluation points per quartile. Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

7 Fig. 5 Correlation of erythrocyte 6-MP metabolite levels with drug-related side effects in IBD. n, number of observations. (A) Correlation of 6-MMP levels with hepatotoxicity. Hepatotoxic events were associated with higher median 6-MMP levels. *P < (B) Correlation of 6-TG levels with leukopenia at times of therapeutic response and failure. *P = leukopenia (■) vs. no leukopenia (●). Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

8 Fig. 5 Correlation of erythrocyte 6-MP metabolite levels with drug-related side effects in IBD. n, number of observations. (A) Correlation of 6-MMP levels with hepatotoxicity. Hepatotoxic events were associated with higher median 6-MMP levels. *P < (B) Correlation of 6-TG levels with leukopenia at times of therapeutic response and failure. *P = leukopenia (■) vs. no leukopenia (●). Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions

9 Fig. 6 Relationship between TPMT genotype and 6-TG level in IBD. Median 6-TG levels were higher among heterozygotes (TPMTH/TMPTL) (n = 8) than homozygous normals (TPMTH/TMPTH) (n = 84) with high-activity (H) alleles. *P < Gastroenterology  , DOI: ( /S (00) ) Copyright © 2000 American Gastroenterological Association Terms and Conditions


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