Prospective Study of the Effects of Concomitant Medications on Thiopurine Metabolism in Inflammatory Bowel Disease

M. Daperno; R. Sostegni; R. Canaparo; L. Serpe; A. Lavagna; L. Crocellá; F. Castagno; A. Vernetto; C. Rigazio; E. Ercole; S. D'Antico; A. Pera; G. Zara; R. Rocca

Disclosures

Aliment Pharmacol Ther. 2009;30(8):843-853.

Abstract and Introduction

Abstract

Background Thiopurines are increasingly used in the treatment of inflammatory bowel disease (IBD), being the most common immunosuppressive therapy; however, potentially harmful interactions between thiopurines and other drugs (especially 5-aminosalicylic acid, 5-ASA) were described.
Aim To explore potential interactions between thiopurines and concomitant medications.
Methods A total of 183 consecutive IBD patients were enrolled. Clinical characteristics and concomitant medications were recorded. Thiopurine metabolism was analysed with thiopurine S-methyl transferase (TPMT) genetic variants and enzyme activity assays. Comparisons were carried out with stratification of patients according to clinical characteristics and active treatments.
Results Based on TPMT genetics, 95% IBD patients were wild-type homozygous, the remaining being heterozygous. Median TPMT activity was 24.9 U/Hgb g (IQR 20.7–29.5). No difference in TPMT activity was noted according to 5-ASA exposure. IBD patients on thiopurines had higher TPMT activity levels, but no dose-effect was evident. No difference in TPMT activity was observed in 41 (63%) patients co-treated with 5-ASA. In patients on active thiopurines also, 6-TGN and 6-MMP levels were evaluated and no significant difference was observed based on co-medication. TPMT activity was independently associated only with thiopurines dose (P = 0.016).
Conclusions Our data suggest the absence of significant interactions between thiopurines and 5-ASA.

Introduction

Thiopurines (azathioprine and mercaptopurine) are extensively used in clinical practice and their use in inflammatory bowel disease (IBD) has increased over the last decades.^[1,2] The effect on clinical outcomes is still a matter of debate, but current guidelines and everyday routine clinical practice include azathioprine or mercaptopurine among the most commonly used drugs, especially because of their steroid-sparing effect.^[3–6] Moreover, their use, together with infliximab, has been advocated and they are therefore an essential therapeutic weapon.^[7]

Metabolism of azathioprine is quite well-known and it includes, after a non-enzymatic step leading to mercaptopurine formation, several enzymatic transformations leading to formation of active metabolites, of toxic intermediate molecules and finally to complete catabolism of the drug. One of the most important steps in thiopurine metabolism is under thiopurine S-methyl-transferase (TPMT, EC 2.1.1.67) control. TPMT is a cytosolic enzyme which catalyses the S-methylation of aromatic and heterocyclic sulphydril compounds.^[8] This enzyme represents one of the most striking examples of the potential of pharmacogenetics to contribute to personalize drug therapy with 89–94% of individuals having high TPMT activity, 6–11% having intermediate activity and approximately 0.3% with extremely low or absent TPMT activity.^[9] Family studies have shown that TPMT activity is inherited as an autosomal codominant trait, with at least 21 TPMT genetic polymorphisms identified, which may be associated with decreased levels of TPMT enzyme activity and/or thiopurine drug-induced toxicity.^[10] Many population studies were carried out to identify the predominant variant alleles and, on the basis of these researches, TPMT*3A and *3C are the predominant variant alleles, with *2 contributing to a lesser extent. These three alleles account for over 95% of cases of inherited TPMT deficiency in Caucasian subjects.^[11]

Five-aminosalicylic acid (5-ASA) is very commonly used in inflammatory bowel disease. Its role is essential in ulcerative colitis treatment, both in induction and in maintenance of remission;^[6] moreover, despite its limited efficacy, 5-ASA is used also in Crohn's disease, especially for prevention of post-surgical relapse.^[5] Finally, another therapeutic goal, which justifies a wide use of 5-ASA, is the potential chemopreventive role in IBD colitis.^[12] A recent population-based study reported an overall prevalence of oral 5-ASA use in up to 75% IBD patients in Northern Italy.^[13]

Some Literature data showed that 5-ASA may lower TPMT activity, thus leading to increased bioavailability of upstream metabolites, with potential toxic effects and/or potential therapeutic gain.^[14–16] In vitro experiments reported substantial inhibition of TPMT activity or effects on thiopurine active metabolites by sulphasalazine or 5-ASA.^[17–19] Consistent with these in vitro data, a few clinical reports suggested that there may be a significant interaction between 5-ASA and TPMT also in vivo and such an interaction may be used to maximize thiopurine therapeutic window.^[20–22]

The aims of the study were to analyse in a consecutive series of IBD patients:

overall TPMT activity and
the effects of thiopurine, 5-ASA and other concomitant IBD medications on TPMT activity and on metabolites levels

to evaluate relevant interactions clinically.

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Abstract and Introduction
Patients and Methods
Results
Discussion
References

Table 1. Descriptive report of characteristics of patient population overall and according to diagnostic category
Clinical characteristic	Crohn's	Ulcerative colitis	Indeterminate	Total
Diagnosis; n (%)	88 (48)	91 (50)	4 (2)	183
Gender: Female; n (%)	49 (56)	38 (42)	2 (50)	89 (49)
Location L1/L2/L3/L4; n (%)	16/42/23/7 (18/48/26/8)	NA	NA	NA
Extension E1/E2/E3; n (%)	NA	32/18/41 (35/20/45)	2/2/0 (50/50/0)	34/20/41 (36/21/43)
Age at diagnosis: years median (IQR)	31 (24–45)	38 (27–48)	46 (39–60)	35 (25–46)
Disease duration; years median (IQR)	9.4 (5.1–17.5)	11.4 (6.4–15.4)	6.3 (4.7–8.9)	10 (5.8–16.4)
Concomitant EIMs; n (%)	32 (36)	24 (26)	1 (25)	57 (31)
Perianal disease; n (%)	24 (27)	1 (1)	0 (0)	25 (14)
BMI; median (IQR)	22.3 (20.5–25)	24.2 (21.3–27.4)	24.2 (21.6–26.9)	23.7 (21–25.9)
Previous surgery; n (%)	44 (50)	6 (7)	0 (0)	50 (27)
Infliximab ever; n (%)	22 (25)	15 (16)	1 (25)	38 (21)
Thiopurine ever; n (%)	40 (45)	54 (59)	1 (25)	95 (52)
Active thiopurine; n (%)	23 (26)	44 (48)	1 (25)	68 (37)
Active 5-ASA; n (%)	60 (67)	69 (76)	4 (100)	133 (72)
Concomitant 5-ASA & thiopurines; n (%)	11 (13)	29 (32)	1 (25)	41 (22)
Activity index*; median (IQR)	161 (79–250)	0 (0–3)	1 (0–2)	NA
Active disease; n (%)	38 (43)	27 (30)	1 (25)	66 (36)

n, number; NA, not applicable; L1/L2/L3/L4, disease location according to Montreal Classification;^[21] E1/E2/E3, extension of disease according to Montreal Classification;^[21] IQR, interquartile range; EIMs, extraintestinal manifestations; BMI, body mass index, kg/m².
* Activity index: CDAI is considered for Crohn's disease patients, and CAI for ulcerative colitis/indeterminate colitis patients; 5-ASA, 5-aminosalycilic acid.

Table 2. Median TPMT activity levels (expressed in U/Hgb g) in different subgroups of patients; for simplification of results and to avoid biases in interpretation of results, only TPMT wild type homozygous are considered. Subgroups are presented as comparator followed by compared subgroup (in brackets)
Subgroups compared	N	Median TPMT	IQR	P
Cases (overall)	174	24.9	20.69–29.45	NA
Crohn's (vs. ulcerative colitis/IC)	83	25.26	21.27–30.17	0.255
Female (vs. male)	86	23.77	20.61–29.64	0.521
Actual age ≤40 years (vs. >40)	59	25.19	21.01–29.05	0.522
BMI <20 kg/m² (vs. 20–27 vs. >27)	31	24.91	21.86–27.86	0.727
Active disease (vs. remission)	64	25.33	21.21–30.54	0.358
CRP > 5 mg/l (vs. ≤ 5)	31	23.56	21.20–29.60	0.911
5-ASA
None	47	25.4	21.41–30.75	0.348
<2 g/day	14	27.38	20.34–28.88
2–3 g/day	93	23.6	19.99–27.17
>3 g/day	20	25.19	22.74–31.86
Azathioprine (active treatment), AZA
None	109	23.19	20.38–27.06	0.022
<1.5 mg/kg b.w./day	15	26.66	21.16–31.04
1.5–2 mg/kg b.w./day	35	26.84	24.22–30.53
>2 mg/kg b.w./day	15	27.74	20.34–33.63
AZA+/5-ASA+ (vs. AZA+/5-ASA−)	41	25.63	21.43–32.13	0.221
AZA+/Crohn's (vs. AZA+/ulcerative colitis/IC)	23	25.63	22.37–30.82	0.698
Adverse effects from AZA (vs. other)	31	23.6	20.68–28.75	0.674
Leukopaenia due to AZA (vs. other)	4	26.87	21.28–28.63	0.850
Infliximab+ (vs. infliximab−)	35	26.94	22.67–32.29	0.049
Steroid+ (vs. steroid−)	19	27.23	18.51–32.80	0.416
Disease duration:
<5 years	34	25.77	22.17–31.96	0.026
5–15 years	87	24.91	21.38–30.31
>15 years	53	22.44	18.94–26.65
Duration azathioprine treatment:
<6 months	12	26.19	22.88–30.82	0.908
6–36 months	30	26.29	21.87–31.73
>36 months	23	26.94	21.67–33.56

N, number of cases in the subgroup; TPMT, thiopurine S-methyl transferase activity, U/Hgb g; IQR, interquartile range; P, P value; vs., versus compared subgroup; NA, not applicable; IC, indeterminate colitis; BMI, body mass index; CRP, C-reactive protein; 5-ASA, 5-amino salicylic acid; AZA+/5-ASA+, azathioprine and 5-ASA active treatment; AZA+/5-ASA−, azathioprine active treatment and no 5-ASA treatment; infliximab+, active infliximab treatment; infliximab−: no active infliximab treatment; steroid+, active steroid treatment; steroid−, no active steroid treatment.

Table 3. Median levels of 6-tioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP), expressed as pMol/8 × 10 ⁸ RBC, in different subgroups of patients; for simplification of results and to avoid biases in interpretation of results, only TPMT wild type homozygous are considered. Subgroups are presented as comparator followed by compared subgroup (in brackets)
Subgroups compared	N	Median 6-TGN	IQR	P	Median 6-MMP	IQR	P
Cases (overall)	65	149.53	84.32–220.29	NA	577.44	186.62–1544.46	NA
Crohn's (vs. ulcerative colitis/IC)	23	143.58	72.22–201.03	0.288	368.91	100.31–831.86	0.014
AZA+/5-ASA+ (vs. AZA+/5-ASA−)	38	157.32	86.19–242.93	0.496	615.01	148.40–1724.32	0.922
Active (vs. remission)	20	171.08	111.83–248.60	0.301	556.21	205.01–1418.82	0.965
Infliximab + (vs. infliximab −)	25	123.98	70.42–197.05	0.177	599.61	149.94–1270.76	0.491
Steroid + (vs. steroid −)	6	159.37	34.88–306.05	0.888	823.44	577.44–1829.04	0.413

N, number of cases in the subgroup; IQR, interquartile range; P, P value; NA, not applicable; vs., versus compared subgroup; IC, indeterminate colitis; AZA+/5-ASA+, azathioprine and 5-ASA active treatment; AZA+/5-ASA−, azathioprine active treatment and no 5-ASA treatment; infliximab +, active infliximab treatment; infliximab−, no active infliximab treatment; steroid+, active steroid treatment; steroid−, no active steroid treatment.

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