Volume 122, Issue 4, Pages 904-915 (April 2002) 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease  Marla C. Dubinsky, Huiying Yang, Philip V. Hassard, Ernest G. Seidman, Lori Y. Kam, Maria T. Abreu, Stephan R. Targan, Eric A. Vasiliauskas  Gastroenterology  Volume 122, Issue 4, Pages 904-915 (April 2002) DOI: 10.1053/gast.2002.32420 Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 1 6-MP metabolism. Oral AZA is rapidly converted to 6-MP by a nonenzymatic process. Initial 6-MP transformations occur along competing catabolic (XO, xanthine oxidase; TPMT, thiopurine methyltransferase) and anabolic (HPRT, hypoxanthine phosphoribosyltransferase) enzymatic pathways. Once formed, 6-thiosine 5'-monophosphate (6-TIMP) may be transformed either into 6-TGN by the rate-limiting inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthetase (GMPS) enzymatic pathways or methylated into 6-MMPR. Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 2 Flow diagram of patient recruitment. A total of 51 patients met the inclusion criteria. Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 3 Effect of dose escalation on 6-TGN levels. Lines connect values from same patient pre- and post-dose adjustment. Graph on left depicts changes among nonresponders, and graph on right depicts those of responders. *6-TGN levels were higher at Time 1 among responders; P = 0.03. Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 4 Association between 6-MP metabolite levels and therapeutic efficacy. Median change in (A) 6-TGN and (B) 6-MMPR levels from baseline (Time 0) to reevaluation after dose escalation (Time 1) among responders (n = 14) and among nonresponders (n = 37). Dark line inside the box represents median values; boxes represent interquartile distance (IQD: 25th and 75th percentiles); lines extending from the box indicate the extreme values of the data or a distance of 1.5 × IQD from the center, whichever is less; and circles represent outliers (observations that are more than 1.5 × QID). *P < 0.0003, §P < 0.0057. Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 5 Correlation between the change in 6-TGN and the change in 6-MMPR levels at Time 1. A negative correlation (r = 0.4, P = 0.003) was observed using Spearman rank correlation test. Responders (X) had a greater positive change in 6-TGN production, and nonresponders (O) experienced greater changes in 6-MMPR. Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 6 Correlation between 6-MP/AZA dose (mg · kg−1 · d−1) and 6-TGN levels at Time 1. Regression analysis showed a positive relationship between dose and 6-TGN (β = 396.7, P = 0.026) among responders (X), yet not among nonresponders (O) (β = 39.5, P = 0.5). AZA dose was converted to 6-MP dose by a factor of 2.07 for analysis.11. Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions

Fig. 7 Median 6-MMPR levels among patients who experienced a hepatotoxic (AST/ALT > 2 × N) event vs. those patients who did not. Hepatotoxic events were associated with higher median 6-MMPR levels. *P < 0.001. Dark line inside the box represents median value; boxes represent interquartile distance (IQD: 25th and 75th percentiles); lines extending from the box indicate the extreme values of the data or a distance of 1.5 × IQD from the center, whichever is less; and circles represent outliers (observations that are more than 1.5 × QID). Gastroenterology 2002 122, 904-915DOI: (10.1053/gast.2002.32420) Copyright © 2002 American Gastroenterological Association Terms and Conditions