Diarrhea

Figure 3 Biotransformation of irinotecan.

UDP-glucuronosyltransferases (UGT), UGT1A1 and UGT1A9, and the extrahepatic UGT1A7, are involved in SN-38 glucuronidation (90).

More than 50 variants have been reported in UGT1A1; many of these are found in patients with Gilbert's syndrome, an inherited condition of impaired bilirubin conjugation, occurring in 5% to 10% of the general population (91). One of the most common genotypes leading to Gilbert's syndrome is UGT1A1 *28, wherein the promoter contains a sequence of [A(TA)7TAA] compared with the wild-type UGT1A1 with a sequence of [A(TA)6 TAA]. The UGT1A1 *28 polymorphism is present in about 40% of the Caucasians of whom 8% have Gilbert's syndrome (92). UGT1A1 *28 is associated with a 70% reduction in transcriptional activity compared with the wild-type UGT1A1. In a case-control study, 46% (12/26) of the patients with severe toxicity due to irinotecan (leukocyte count <0.9 x 10/l or diarrhea >5 days/bloody diarrhea/diarrhea with dehydration) were carrying the UGT1A1 *28 allele (either heterozygous or homozygous), compared with 14% (13/92) of the controls (93). Multivariate analysis suggested that subjects carrying UGT1A1*28 were seven times more likely to get irinotecan toxicity. All three patients heterozygous for UGT1A1 *27 also suffered adverse effects, whereas there was no association with UGT1A1*6. None of the subjects in the study had UGT1A1 *7 or UGT1A1 *29 alleles, and hence their role could not be evaluated (93).

UGT1A7 is the most efficient of the UGTs in metabolizing SN-38 (90). The influence of the UGT1A7 genotype in predisposing to irinotecan toxicity may be different to that due to Gilbert's syndrome (87). UGT1A7 is not expressed in the small or large intestine, unlike UGT1A1 (94). Thus, the majority of the SN-38 in the intestine results from cleavage of SN-38 glucuronide by bacterial ^-glucuronidase allowing reabsorption of SN-38 (86). Therefore, extensive metabolizers with a UGT1A7*1 or UGT1A7*2 genotype may have reduced plasma SN-38 levels but may still be at increased risk of gastrointestinal toxicity because of increased fecal SN-38 after deconjugation of SN-glucuronide (87). Common variants of UGT1A7, UGT1A7*3 (N129K;R131K;W208R), and UGT1A7*4 (W208R) could be at risk of bone marrow suppression as they are associated with reduced SN-38 glu-curonidation. However, a recent case-control study has not shown any association between the UGT1A7 genotype and irinotecan-induced adverse reactions (95).

Adverse Reactions Involving the Liver

Because the liver is central to the biotransformation of virtually all drugs and foreign substances, drug-induced liver injury is a potential complication of nearly every medication that is prescribed. The liver is the most common target organ for toxicity encountered during the course of drug development (96). Despite considerable progress in toxicologi-cal studies, the correlation between liver toxicity in animals and man remains poor (97). As the "high-risk" agents have been replaced, relatively rare reactions to commonly prescribed "low-risk" agents have contributed to the total burden of the drug-induced liver disease (98). The incidence of symptomatic hepatic ADRs is estimated to be 14 per 100,000 population, 16 times greater than the number noted by spontaneous reporting to the regulatory authorities (99). Adverse hepatic drug reactions have been the leading cause of postmarketing withdrawals in the last four decades (98,100).

The basic mechanism underlying drug-induced hepatotoxicity is considered to be metabolic or immunologic idiosyncrasy. Metabolic idiosyncrasy implies that the patient developing the adverse reaction metabolizes the drug in a different way than most individuals or lacks adequate protective mechanisms to neutralize any reactive metabolites that are formed. Immunologic idiosyncrasy implies that the susceptible individual has an immune system that would more readily recognize any formed neoantigens. Genetic factors influencing the development of drug-hepatotoxicity can be grouped into factors affecting the amount of reactive metabolite formed and therefore the levels of the protein adduct, and factors affecting the immune response to the adducts.

Metabolic Idiosyncrasy. Initial studies investigating the role of DME polymorphisms in drug-induced liver disease used phenotyping experiments in small groups of patients. Polymorphism in debrisoquine oxidation (CYP 2D6) has been shown to result in accumulation of perhexiline, leading to liver injury in poor metabolizers (101), and to increase the formation of reactive metabolites, leading to chlorpromazine hepatotoxi-city in extensive metabolizers (102). Defective hepatic sulfoxidation has also been shown to contribute to chlorpromazine jaundice (102). Polymorphism in mephenytoin hydroxylation (CYP 2C19) has been associated with Atrium (phenobarbital, febarbamate, and difebarbamate)-induced hepatotoxicity, with poor metabolizers being at increased risk (103). More recently, genotyping for drug metabolizing enzyme gene polymorphisms has been used to study genetic susceptibility to drug-induced liver disease.

Isoniazid hepatotoxicity. The growing prevalence of drug-resistant Mycobacter-ium tuberculosis strains and the increasing number of patients with acquired immunodeficiency syndrome (AIDS) has lead to the worldwide resurgence of tuberculosis. Regimens containing isoniazid, rifampicin, ethambutol, and pyrazinamide are used as first-line therapy for tuberculosis. The incidence of antituberculosis drug-induced hepatotoxicity varies from 13% to 36% in different populations (104-107), with a 1% to 10% case-fatality rate. Isoniazid is the major drug incriminated, and liver injury secondary to this drug continues to be reported worldwide (108-111).

The enzyme N-acetyltransferase (NAT) is responsible for the metabolism of isoniazid to acetylisoniazid, which in turn is hydrolyzed to acetyl hydrazine (Fig. 4) (112). The latter could be oxidized by CYP2E1 to form N-hydroxy-acetylhydrazine, which further dehydrates to yield acetyldiazene. Acetyldiazene may itself be the toxic metabolite or may break down to the reactive acetylonium ion, acetyl radical, and ketene, which could bind covalently to hepatic macromolecules resulting in liver injury (112-114). NAT is also responsible for further acetylation of acetylhydrazine to the nontoxic diace-tylhydrazine. Therefore, slow acetylation results not only in accumulation of the parent compound but also of monoacetylhydrazine. Acetylation of acetylhydrazine is further suppressed by isoniazid itself. In addition, direct hydrolysis of isoniazid without acetylation

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