M eth y 1 mere aptop u r i n e

?hepatotoxic

Figure 2 Metabolism of azathioprine and 6-mercaptopurine.

result from two substitutions at position 460 (G460A, Ala-to-Thr) and at position 719 (A719G, Tyr-to-Cys), resulting in the TPMT*3A (both G460A and A719G) and TPMT*3B (only G460A) genotypes (44-46). These genotypes account for 75% of the variant alleles associated with absence of catalytic activity.

Both measurement of erythrocyte TPMT activity and genotyping have been used in optimizing azathioprine or 6-mercaptopurine therapy in patients with inflammatory bowel disease. Dubinsky et al. (47) in a study of 92 pediatric IBD (inflammatory bowel disease) patients (79 with Crohn's disease) reported higher 6-thioguanine levels in patients heterozygous for TPMT (TPMTh/TPMTl), all of whom responded to therapy. A prospective study thereafter demonstrated that measurement of 6-thioguanine levels could be used to achieve remission in patients with Crohn's disease who had initially failed to respond to conventional dosing with azathioprine (48). However, a large study of 170 patients (130 with Crohn's disease) found no correlation between 6-thioguanine nucleotide levels and disease activity, as measured by an inflammatory bowel disease questionnaire. However, the study design led to the inclusion of only those who had responded to and tolerated the treatment and hence would not have allowed evaluation of the role of measuring 6-thioguanine levels in the management of inflammatory bowel disease (49). Overall, the strength of the observed correlation between 6-thioguanine nucleotide levels and therapeutic efficacy suggests that monitoring metabolites may identify those patients not responding to azathioprine or 6-mercaptopurine because of either inadequate dosing or noncompliance (41).

Metabolic variability also appears to influence the prevalence of adverse reactions. Reduced TPMT activity and high 6-thioguanine levels have been associated with azathioprine-induced leukopoenia (47,50). Variant TPMT allele can be found in up to 27% of the patients with Crohn's disease who develop myelosuppression, and the toxicity appears early in the course of treatment (within six weeks) in subjects homozygous for the variant allele (51). In a subgroup of patients with inflammatory bowel disease who fail to respond to azathioprine/6-mercaptopurine therapy, dose escalation does not result in optimal 6-thioguanine nucleotide production but rather results in the preferential production of 6-methyl mercaptopurine ribonucleotide, which has been associated with hepatotoxicity (47,52).

CYP2C19 Polymorphism and Efficacy of Proton Pump Inhibitors. Proton pump inhibitors, such as omeprazole and lansoprazole, are mainly metabolized by CYP2C19 in the liver. Rabeprazole is nonenzymatically converted largely to thioether-rabeprazole and partially metabolized to demethyl rabeprazole by CYP2C19. The variant alleles CYP2C19m1 (G to A substitution in exon 5 at position 681, which produces a cryptic splice site resulting in a truncated nonfunctional protein) and CYP2C19m2 (G to A substitution in exon 4 at position 636, which creates a premature stop codon) are responsible for the CYP2C19 poor metabolizer phenotype (53,54). CYP2C19m1 is found in both Asians and Caucasians, but CYP2C19m2 is not found in Caucasians. The effects of lansoprozole, omeprazole, and rabeprazole on intragastric pH have been shown to dependent on the CYP2C19 genotype (55,56). Studies in small groups of patients have shown that Helicobacter pylori eradication rate on dual therapy (combination of proton pump inhibitor and amoxicillin) was significantly higher in those homozygous for the poor metabolizer genotypes (57,58). However, the CYP2C19 genotype did not significantly affect cure rates for H. pylori infection by triple therapy (combination of proton pump inhibitor, amoxicillin, and clarithromycin) (59). CYP2C19 genotype also seems to partly determine the efficacy of lansoprazole in gastroesophageal reflux disease: patients homozygous for the extensive metabolizer genotype had the lowest plasma lansoprazole levels and the lowest cure rate (60). Overall, however, the influence of the CYP2C19 genotype on efficacy of proton pump inhibitor therapy is likely to be greatest in Asians, where the frequency of the poor metabolizer phenotype is five times greater compared with the Caucasians.

Genetic Polymorphisms in Drug Targets

Drugs usually exert their effects via an interaction with membrane receptors (about 50% of drugs), enzymes (about 30%), or ion channels (about 5%) (61). Many of the genes encoding these drug targets exhibit genetic polymorphisms, which alter their sensitivity to the medication and thereby response to therapy. Mutations in transporters involved in the reuptake of neurotransmitters may alter neurotransmitter levels within the synaptic cleft and thereby lead to an altered response to both agonists and antagonists.

Serotonin-Transporter Polymorphism and Response to Alosetron. Irritable bowel syndrome affects about 15% of the adults (62). Diarrhea-predominant irritable bowel syndrome is associated with an accelerated transit and rectal hypersensitivity. Serotonin (5-HT) modulates the sensorimotor function in the digestive tract with the 5-HT type 3 receptors, in particular, mediating the postprandial colonic motor response (63), which is often associated with cramping, urgency, and diarrhea in patients with the syndrome. Alosetron, a 5-HT3 receptor antagonist, results in the relief of pain and normalization of bowel function in women with diarrhea-predominant irritable bowel syndrome (64,65).

5-HT undergoes reuptake by a transporter protein (SERT), which controls its activity locally. A 44-base pair insertion/deletion polymorphism, approximately 1-kb upstream of the serotonin transporter gene SERT, has been identified (66). Homozygosity for the short variant results in less transcript, less protein expression, and hence less re-uptake of serotonin (66,67). In a study involving 30 patients, the SERT polymorphism was associated with the colonic transit response to alosetron (68) with the long homozy-gous patients showing greater response (slowing of colonic transit) to alosetron, compared with the heterozygous patients.

Polymorphisms in HCV and Response to Interferon. The efficacy of interferon therapy in HCV infection varies depending on viral genotype; infection with genotype 1b is associated with a sustained virologic response in 10% to 25% of the patients (69). The efficacy of interferon therapy in HCVlb infection can be predicted based on the HCV RNA levels and the number of amino acid mutations in the interferon sensitivity-determining region (ISDR in the 2209 to 2248 region of NS5A gene) (70-72). A recent study using a decision analysis model showed that interferon therapy was not useful in patients aged 50 to 60 years with HCV-lb infection without mutations in the interferon sensitivity-determining region and HCV RNA levels exceeding 1.0 mEq/mL (73).

Genetic Susceptibility to Adverse Drug Reactions

An adverse drug reaction (ADR) is defined as any response to a drug that is noxious, unintended, and occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease (74). ADRs result in significant morbidity, mortality, and excess medical care costs. In the United States, more than two million hospitalized patients suffer serious ADRs annually (75). There are many different types of ADRs (chap. 5). "Idiosyncratic," or type B, ADRs are not predictable from a knowledge of the pharmacology of the drug, and mechanisms are not clearly understood. A postulated mechanism involves covalent binding of reactive metabolites to proteins, which then either directly interferes with cellular function resulting in cytotoxicity or induces an immune response (76,77). Susceptibility to ADRs could therefore theoretically depend on genetic factors that determine the metabolism and also on the biochemical and immunological responses to the metabolites. It is therefore likely that drug therapy based on an individual's genetic make-up may result in a clinically important reduction in ADRs (4).

Gastrointestinal Adverse Drug Reactions

Of the many different types of adverse reactions that can be induced by drugs, gastrointestinal ADRs are the commonest cause of hospital admission (78), accounting for about 18% of cases (79,80). Although gastrointestinal bleeding, nausea, vomiting, and antibiotic-induced diarrhea account for the majority of the events, a wide variety of other drug-induced gastrointestinal adverse effects have also been reported.

Irinotecan Toxicity. Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] car-bonyloxy camptothecin or CPT-11) is an anticancer agent that inhibits topoisomerase I activity (81). Clinical trials have established the role of irinotecan (in combination with 5-fluorouracil/leucovorin) in the treatment of metastatic colorectal cancer (82,83). The most common adverse effects of irinotecan are bone marrow toxicity and ileocolitis leading to diarrhea (84). These adverse effects may lead to the discontinuation of an otherwise effective anticancer treatment.

Irinotecan is a prodrug—metabolism by tissue and serum carboxylesterases generates the more active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) (85). Metabolism of SN-38 by glucuronidation and subsequent elimination through biliary excretion is the primary route of detoxification (Fig. 3) (86). Diarrhea due to irinotecan therapy is due to the toxic actions of unconjugated SN-38 on the intestinal mucosa. SN-38 can be absorbed into epithelial cells from both the basolateral (blood) and apical (luminal side) surfaces, targeted for glucuronidation, and effluxed back into the lumen (87). There is an inverse relationship between SN-38 glucuronidation rates and severity of diarrhea in patients treated with irinotecan (88,89). Two major hepatic

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