Asians CYP2C19 polymorphisms

The clinical relevance of the CYP2C19 polymorphism, primarily present in Asian populations (4), has been studied by a number of investigators who have shown that the cure rate for Helicobacter -pylori infection is greater in patients who are genetic poor metabolizers (5). When given omeprazole doses of 20 mg/day for 4 weeks, these individuals have plasma areas under... 

Polymorphisms of CYP2C19 cause differences in metabolism of omeprazole, a proton pump inhibitor used for treatment of gastroduodenal ulcers or reflux esophagitis. Such polymorphisms result in resistance to treatment at a standard dose regimen in nearly 20% of European Caucasians, and in an even higher percentage of Asians [12]. 

CYP2C18 has been examined as a candidate for the (S)-mephenytoin 4 -hydroxylase polymorphism. Romkes et al. (1991) demonstrated that cDNA-expressed CYP2C18 4 -hydroxylated (5)-mephenytoin at a rate above background. However, CYP2C19 has recently been established as the protein responsible for the (5)-mephenytoin 4 -hydroxylase polymorphism (Wrighton et al., 1993 Goldstein et al., 1994). Population studies have demonstrated that 3-5% of Caucasians and about 20% of Asians are poor metabolizers of (5)-mephenytoin (Kalow, 1986). The molecular basis for this polymorphism has recently been established (de Morals et al., 1994). 

Drugs that are metabolized by the cytochrome P-450 (CYP) isoenzymes CYP2D6, CYP2C9, and CYP2C19 also exhibit genetic polymorphisms. An example of CYP2D6 metabolism is debrisoquine. In about 5-10 /o of Caucasians in North America and Europe and about 1% of Asians, 4-hydroxylation of debrisoquine is reduced, and such individuals are at increased risk for toxicity (orthostatic hypotension). Beta blockers (metoprolol and timolol), antiarrhythmic drugs (encainide and flecainide), tricyclic antidepressants... 

CYP2C19 (mephenytoin hydroxylase) is also associated with marked interethnic differences. This enzyme metabolizes diazepam and several antidepressants (Pi and Gray 1998). Between 2% and 10% of whites have little or no activity of this enzyme, whereas 15%-25% of Asians maybe PMs (Horaietal. 1989 Kupfer and Preisig 1984 Pi and Gray 1998). In addition, there is also evidence of polymorphism among EMs, with some Asian EMs having a form of the enzyme with less activity than that of the form commonly found in Caucasian EMs (Sjoqvist et al. 1997). 

CYP2C19 [68] is also a polymorphic gene located on chromosome 10, with three major alleles. The most frequent allele is 1 and it has normal activity. Two alleles with no activity, 2 and 3, were initially described. The 2 allele is particularly frequent in East Asians approximately 10% to 25% of East Asians are CYP2C19 PMs. Less than 5% of subjects from other races are CYP2C19 PMs [68]. Alleles 4 to 8 are inactive but... 

Plasma elimination t is 6 hours. Voriconazole exhibits nonlinear kinetics, and higher doses disproportionately increase drug exposure. Genetic polymorphisms in CYP2C19 can cause up to a fourfold difference in drug exposure -20% of Asians are poor metabolizers compared to 2% of Caucasians and African Americans. Drug exposure is increased considerably in the elderly and in patients with mild or moderate hepatic insufficiency. Patients with hepatic cirrhosis should receive the same loading dose of voriconazole but half the maintenance dose. 

The main metabolic pathway for esomeprazole, lansoprazole, omeprazole, pantoprazole, and to a lesser extent rabeprazole, is through the cytochrome P450 isoenzyme CYP2C19. This isoenzyme is subjeetto genetic polymorphism, (see Genetic factors , (p.4), for a further explanation of polymorphism). The poor metaboliser phenotype for CYP2C19 is found in approximately 1 to 6% of Caucasians, 1 to 7.5% of Blacks and 12 to 23% of Oriental and Indian Asians. ... 

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