Inter‐ethnic and inter‐phenotype differences among Ghanaians and Caucasians in the metabolic hydroxylation of phenytoin [proceedings]

Andoh, B; Idle, J R; Sloan, T.P.; Smith, Roger; Woolhouse, N. M.

doi:10.1111/j.1365-2125.1980.tb04842.x

Cited by 13 publications

(4 citation statements)

References 3 publications

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“…Of special interest is a study of phenytoin oxidation in Ghanaians and Caucasians in relation to the status of debrisoquine hydroxylation capacity (Andoh et al, 1980). In each population, poor metabolisers of debrisoquine excreted somewhat less p-hydroxyphenytoin in their urine than did the extensive metabolisers.…”

Section: Debrisoquinementioning

confidence: 99%

Ethnic Differences in Drug Metabolism

Kalow

1982

Clinical Pharmacokinetics

205

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Interethnic differences in drug-metabolising capacity may be substantial, and they are sufficiently frequent to warrant attention. Such differences may consist of different mean values of quantitative traits in separate populations, or of different frequency distributions as produced by the occurrence of genetic enzyme variants. The collection of population data requires the investigation of substantial numbers of subjects. This may be no problem if drug-metabolising enzymes occur in blood or are sufficiently stable in their tissues to allow investigation in vitro. However, if investigations require the use of probe drugs, new efforts are needed to adapt pharmacokinetic methods to make them suitable for population studies. This development of methods is further called for because genetic variants seem to be more easily detected through the assessment of particular metabolites than through the determination of pharmacokinetic parameters of the parent drug. Many studies with probe drugs comparing different populations have given results that are equivocal in terms of the nature-nurture interplay. However, a set of data with antipyrine has pointed to environmental factors as the principal determinant of differences in metabolising capacity, while data with debrisoquine have indicated monogenically controlled variation of one facet of the cytochrome P-450 system. In several instances, statistically significant differences between population means have been established by testing small numbers of subjects, numbers insufficient to establish distribution patterns that would allow the recognition of genetic polymorphism. The populations studied range from Greenlanders to South African Blacks, but most comparisons pertain to Caucasians and Orientals.

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Section: Debrisoquinementioning

confidence: 99%

Ethnic Differences in Drug Metabolism

Kalow

1982

Clinical Pharmacokinetics

205

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“…A. J. H. Critchley et al been reported in Caucasians. Ghanaians have a reduced capacity for the hydroxylation of debrisoquine (Woolhouse et al, 1979) and possibly phenytoin (Andoh et al, 1980) but not nortriptyline (Woolhouse et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Inter‐subject and ethnic differences in paracetamol metabolism.

Critchley¹,

Nimmo²,

Gregson³

et al. 1986

Brit J Clinical Pharma

135

104

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The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.

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“…The metabolism of a number of drugs has been shown not to co-segregate with that of SP/DB (Brssen & Gram 1989). Initial reports of a significant relationship between debrisoquine 4-hydroxylation and phenytoin p-hydroxylation seen in both Caucasians and Ghanaians (Andoh et al 1980) have not been confirmed (Roots et al 1985;Steiner et al 1987). In a second example, a ten fold higher excretion of the sulphoxide metabolites of carbocysteine in EMS compared to PMs (Waring et al 1981) was subsequently shown to be a chance observation but with a probability of P < 0.001 (Haley et al 1985).…”

Section: Population Panel and Family Studies Of Sparteine And Debrismentioning

confidence: 98%

Genetic Polymorphism of Sparteine/Debrisoquine Oxidation: A Reappraisal

Lennard

1990

Pharmacology & Toxicology

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Polymorphic oxidation of the sparteine/debrisoquine-type has been shown to account for much of the interindividual variation in the metabolism, pharmacokinetics and pharmacodynamics of an increasing number of drugs, including some antiarrhythmic, antidepressant and beta-adrenoceptor antagonist agents. Impaired hydroxylation of these drugs results from the absence of the enzyme cytochrome P450IID6 in the livers of poor metabolisers, who constitute 6% to 10% of Caucasian populations. The clinical importance of the phenomenon has to be explored further and for most sparteine/debrisoquine-related substrates there is a need for controlled prospective studies to define the consequences to the patient of impaired or enhanced drug oxidation.The eficacy, duration of action and toxicity of many lipophilic drugs is governed by their oxidative metabolism. This process is catalysed predominantly by the hepatic cytochrome P-450 enzyme family, the activities of which display pronounced interindividual variation. Cytochrome P-450 activity is regulated by one or more genes and can be modified by environmental and physiological factors.Pathways of drug metabolism that are under monogenic control may exhibit polymorphism within a population. Genetic polymorphsm is defined as the inheritance of a trait controlled by a single genetic locus with two alleles, in which the least common allele has a frequency of about 1 YO or greater. The existence of at least two polymorphisms of drug oxidation has been established unequivocally. They affect the metabolism of the prototype drugs sparteine and debrisoquine (Eichelbaum & Gross 1990) and that of mephenytoin (Kiipfer & Preisig 1984;Wedlund et al. 1984). L(-bsparteine is an alkaloid, which was used clinically to stimulate uterine contractions and as an antiarrhythmic agent. Following the occurrence of serious adverse reactions arising from an exaggerated pharmacological response (Newton et al. 1966), the clinical use of sparteine ceased in the mid 1960's. During the course of studies on its pharmacokinetics and antiarrhythmic effects it was noted that two subjects complained of dizziness, headache, blurred vision and diplopia and that these individuals had plasma drug concentrations four to five times higher than other subjects taking the same dose (Eichelbaum 1975). The results of subsequent population and family studies supported the hypothesis of a genetically impaired oxidation of sparteine (Eichelbaum 1975). Genetic polymorphism of the 4-hydroxylation of debrisoquine was discovered in similar fashion to but independently from that of sparteine (Mahgoub et al, 1977; Tucker et ai. 1977), and it was only later that polymorphic metabolism of the two drugs was found to reflect the same phannacogenetic process (Bertilsson et al. 1980).Since its discovery in 1975, the sparteineldebrisoquine (SP/DB) polymorphism has been studied intensively. After a brief summary of initial studies performed to establish the polymorphic oxidation of SP/DB this review will discuss the relationship bet...

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Inter‐ethnic and inter‐phenotype differences among Ghanaians and Caucasians in the metabolic hydroxylation of phenytoin [proceedings]

Cited by 13 publications

References 3 publications

Ethnic Differences in Drug Metabolism

Ethnic Differences in Drug Metabolism

Inter‐subject and ethnic differences in paracetamol metabolism.

Genetic Polymorphism of Sparteine/Debrisoquine Oxidation: A Reappraisal

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