DRUG METABOLISM, POOR, CYP2D6-RELATEDDRUG METABOLISM, ULTRARAPID, CYP2D6-RELATED, INCLUDED
General Information (adopted from Orphanet):
Synonyms, Signs:
NORTRIPTYLINE, POOR METABOLISM OF, INCLUDED
CODEINE, ULTRARAPID METABOLISM OF, INCLUDED
DEBRISOQUINE, POOR METABOLISM OF, INCLUDED
DEBRISOQUINE, ULTRARAPID METABOLISM OF, INCLUDED
SPARTEINE, POOR METABOLISM OF, INCLUDED
Debrisoquine is an adrenergic-blocking medication used for the treatment of hypertension. Oral legend has it that the poor metabolizer phenotype was discovered when the head of the pharmacology unit in England that was testing debrisoquine as an antihypertensive ... Debrisoquine is an adrenergic-blocking medication used for the treatment of hypertension. Oral legend has it that the poor metabolizer phenotype was discovered when the head of the pharmacology unit in England that was testing debrisoquine as an antihypertensive agent collapsed with vascular hypotension on taking a trial dose of the new drug. He was found to be a 'poor metabolizer' (PM), showing greater sensitivity to the antihypertensive effects of the drug (Idle et al., 1978). Mahgoub et al. (1977) found a sharp bimodality in the ratio of urinary debrisoquine to its oxidized metabolite 4-hydroxydebrisoquine in individuals after an oral dose of 10 mg of debrisoquine. About 3% of the study population were poor or nonmetabolizers, and the authors showed that a polymorphism in hydroxylation of the drug was responsible. Family data suggested that the poor metabolizers were homozygous for a recessive gene, although an extensive and systemic family study was not reported. Gonzalez et al. (1988) described 2 phenotypes: poor metabolizers and extensive metabolizers (EM) of debrisoquine. EM individuals, displaying the wildtype phenotype (and presumably genotype), excreted 10 to 200 times more of the urinary metabolite 4-hydroxydebrisoquine than poor metabolizers. The phenotype extended to the metabolism of more than 25 commonly prescribed medications including neuroleptics, antidepressants, and beta-adrenergic blockers (Johansson et al., 1993). Waring et al. (1981) suggested that sulfoxidation of mucodyne may be regulated by the same gene that controls the oxidation of debrisoquine. Poor hydroxylators of debrisoquine also have impaired metabolism of many other drugs such as phenacetin, nortriptyline, phenformin, sparteine, encainide, propranolol, bufuralol, guanoxan, perhexilene, and amitriptyline (Mellstrom et al., 1981; Oates et al., 1982; Inaba et al., 1980; Harmer et al., 1986). Lennard et al. (1982) demonstrated that metabolism of metoprolol, a beta-1-selective adrenoceptor antagonist, exhibited genetic polymorphism of the debrisoquine type. In patients taking the same dose, they found a 17-fold difference in plasma concentrations of metoprolol. Moreover, poor hydroxylators needed only a single daily dose of metoprolol for therapeutic effect, whereas extensive hydroxylators needed 2 or 3 doses a day. Lennard et al. (1983) identified at least 14 other drugs that are metabolized by CYP2D6 including the antiarrhythmic agent propafenone, a sodium-channel blocker with some structural similarity to propranolol. Lee et al. (1990) presented evidence that genetically determined variations in the conversion of propafenone to its 5-hydroxy metabolite accounts for variations in the drug's beta-blocking action. Slow converters (poor metabolizers) showed greater beta-blockade. Gonzalez et al. (1988) showed that poor metabolizers have negligible amounts of the cytochrome P450DB1 protein (CYP2D6). Nebert (1997) estimated that CYP2D6 may be involved in the metabolism of as many as 20% of all commonly prescribed drugs. - Ultrarapid Metabolizers In addition to deficient hydroxylation of debrisoquine, the opposite phenomenon exists; certain individuals metabolize debrisoquine and several other commonly used drugs very rapidly, resulting in subtherapeutic plasma concentrations at normal doses. Bertilsson et al. (1985, 1993) reported cases in which higher than normal doses of drugs were required to attain therapeutic concentrations. Baumann et al. (1998) reported a patient with depression in whom much higher than usual doses of conventional antidepressants were required. Kawanishi et al. (2002) described a patient with treatment-resistant schizophrenia.
In 20 individuals with poor metabolism of debrisoquine, Gough et al. (1990) identified a splice site mutation in the CYP2D6 gene (124030.0001), yielding a protein with no functional activity. This allele has been ... - Poor Metabolizers In 20 individuals with poor metabolism of debrisoquine, Gough et al. (1990) identified a splice site mutation in the CYP2D6 gene (124030.0001), yielding a protein with no functional activity. This allele has been termed CYP2D6*4. In 2 unrelated poor metabolizer individuals, Gough et al. (1990) and Gaedigk et al. (1991) identified a homozygous 11.5-kb deletion associated with deletion of the entire CYP2D6 gene (124030.0002) and total absence of P4502D6 protein in the liver. This allelic variant is also known as CTP2D6*5. - Ultrarapid Metabolizers The ultrarapid metabolizer patients reported by Bertilsson et al. (1993), Baumann et al. (1998) and Kawanishi et al. (2002) all had a duplication of the CYP2D6 gene. This mutation resulted in excessive activity of CYP2D6, which metabolizes various commonly used neuroleptics, such as haloperidol, risperidone, thioridazine, and perphenazine. In a family in which 2 sibs and their father had MRs of less than 0.02 (ultrarapid metabolizer phenotype), Johansson et al. (1993) found 12 extra copies of the CYP2D6 gene inherited in an autosomal dominant pattern. In a second family in which 2 sibs had MRs of less than 0.1, the authors found 2 extra copies of the CYP2D6 gene. All affected individuals had a variant CYP2D6 gene, termed CYP2D6L (124030.0007). Gasche et al. (2004) described a patient who had developed life-threatening opioid intoxication after he was given small doses of codeine for the treatment of cough associated with bilateral pneumonia. CYP2D6 genotyping showed 3 or more functioning alleles, as a result of gene duplication (124030.0008), resulting in high levels of morphine and morphine-6 glucuronide. Reduction in CYP3A4 (124010) activity by other medications and acute renal failure causing glucuronide accumulation were also factors in the codeine toxicity. Codeine is ineffective at usual doses in 7 to 10% of the white population because of homozygosity for nonfunctional mutant CYP2D6 alleles (Desmeules et al., 1991). The concentration of O-demethylated metabolites can be as much as 45 times as high in persons with ultrarapid CYP2D6 metabolism as it is in those with poor metabolism (Yue et al., 1997).
Evans et al. (1980) estimated the frequency of the poor hydroxylator phenotype to be about 9% in the United Kingdom, but it varies widely among ethnic groups, being about 1% in Arabs and 30% in Hong Kong Chinese ... Evans et al. (1980) estimated the frequency of the poor hydroxylator phenotype to be about 9% in the United Kingdom, but it varies widely among ethnic groups, being about 1% in Arabs and 30% in Hong Kong Chinese (Kalow, 1982). The incidence of poor metabolizers of debrisoquine is between 5 and 10% in the white population of Europe and North America (24:Gonzalez et al., 1988). Zhou et al. (1989) found that Chinese subjects had at least a 2-fold greater sensitivity to the beta-blocking effects of propranolol than white subjects, as measured by the mean plasma concentrations that produced a reduction in heart rate and blood pressure. The Chinese group metabolized propranolol more rapidly than the white group, which resulted in a 76% higher clearance of an oral dose. In addition, the Chinese group had a 45% higher free fraction of propranolol in plasma, which may have contributed somewhat to the increased drug effect.