Debrisoquine oxidation in an Australian population.

Peart, GF; Boutagy, John; Shenfield, Gillian M.

doi:10.1111/j.1365-2125.1986.tb02827.x

Cited by 36 publications

(8 citation statements)

References 13 publications

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“…In a large Swedish study the incidence of poor hydroxylators of mephenytoin was 2.8%; debrisoquine was 8.9% (5). This is similar to data previously reported (7)(8)(9)(10)(11)(12)(13) and our own study. To maximize the detection of differences in hydroxylation capacity migraineurs were not allowed to take drugs known to be metabolized by the probes (14)(15)(16)(17)(18)(19)(20).…”

Section: Discussionsupporting

confidence: 91%

Cytochrome P-450-Dependent Hydroxylation in Migraine

Dahlöf¹,

Alm²,

Bertling³

et al. 1992

Cephalalgia

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The hypothesis was tested that an acute oxidation deficiency related to potential dietary trigger factors plays a role in the migraine attack. Migraine sufferers (14F and 4M), fulfilling the criteria for migraine with and without aura according to the classification of the International Headache Society, were coadministered oral mephenytoin (100 mg) and debrisoquine (10 mg) during the initial phase of a typical migraine attack. This was repeated during a period without migraine. The hydroxylation of mephenytoin and debrisoquine hydroxylation did not differ during and without the migraine attack. We conclude that hydroxylation, via cytochrome P-450 (2D6, 2C8 and 9), is not reduced during the migraine attack. The results do not support the hypothesis that oxidation deficiency is involved in the pathophysiology of migraine.

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Section: Discussionsupporting

confidence: 91%

Cytochrome P-450-Dependent Hydroxylation in Migraine

Dahlöf¹,

Alm²,

Bertling³

et al. 1992

Cephalalgia

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“…About 5 to 10% of the Caucasian population (Brosen et al 1985;Dick et al 1982;Eichelbaum et al 1979;Evans et al 1980;Peart et al 1986;Schmid et al 1985;Steiner et al 1985;Syvalahti et al 1986;Wedlund et al 1984) and about 0 to 0.7% of the Japanese and Chinese have an impaired ability to eliminate debrisoquine and are termed poor metabolisers (Horai et al 1989;Luo et al 1987;Nakamura et al 1985). The polymorphic ability to oxidise debrisoquine is a major factor in determining the pharmacological and toxicological effects of many drugs, including {3-blockers.…”

Section: Consequences Of Debrisoquine Polymorphism On the Dispositionmentioning

confidence: 97%

Ethnic Differences in Drug Disposition and Responsiveness

Wood

Zhou

1991

Clinical Pharmacokinetics

148

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Interethnic differences are important factors accounting for interindividual variations in drug responsiveness. However, these differences in drug response have been a relatively neglected area of investigation, so that similar doses are prescribed to different ethnic populations without consideration of interethnic pharmacokinetic and pharmacodynamic variation. With the increased recognition of genetically determined polymorphism in metabolising ability as an important factor in drug disposition, concern has developed for the importance of individualising drug dose to account for racial differences. The recognition of these differences in drug disposition and responses calls into question the failure of drug licensing authorities to demand information on dosage, efficacy and toxicity in different ethnic groups, and to accept data from limited ethnic groups such as Caucasians. This article reviews the evidence for ethnic differences in drug disposition and sensitivity and should encourage further investigations to elucidate the extent of such differences, their causes and their therapeutic impact.

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“…The results of this theoretical study together with experimental data for debrisoquine (Steiner et al 1985) indicate that heterozygotes can only be identified unequivocally by pedigree analysis. Jackson et al (1986) also predicted that the time of urine collection would make very little difference to the shape and position of the frequency distribution, a finding which has been verified experimentally for debrisoquine (Peart et al 1986).…”

Section: Theoretical Aspectsmentioning

confidence: 78%

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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Debrisoquine oxidation in an Australian population.

Cited by 36 publications

References 13 publications

Cytochrome P-450-Dependent Hydroxylation in Migraine

Cytochrome P-450-Dependent Hydroxylation in Migraine

Ethnic Differences in Drug Disposition and Responsiveness

Genetic Polymorphism of Sparteine/Debrisoquine Oxidation: A Reappraisal

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