Cytochrome P450 2D6 (CYP2D6) metabolizes many important drugs CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on at least 16 different known alleles Their frequencies were determined in 589 unrelated German volunteers and correlated with enzyme activity measured by phenotyping with dextromethorphan or debrisoquine For genotyping, nested PCR-RFLP tests from a PCR amplificate of the entire CYP2D6 gene were developed The frequency of the CYP2D6*1 allele coding for extensive metabolizer (EM) phenotype was 364 The alleles coding for slightly (CYP2D6*2) or moderately (*9 and *10) reduced activity (intermediate metabolizer phenotype [IM]) showed frequencies of 324, 018, and 015, respectively By use of novel PCR tests for discrimination, CYP2D6 gene duplication alleles were found with frequencies of 005 (*1x2), 013 (*2x2), and 001 (*4x2) Frequencies of alleles with complete deficiency (poor metabolizer phenotype [PM]) were 207 (*4), 020 (*3 and *5), 009 (*6), and 001 (*7, *15, and *16) The defective CYP2D6 alleles *8, *11, *12, *13, and *14 were not found All 41 PMs (70%) in this sample were explained by five mutations detected by four PCR-RFLP tests, which may suffice, together with the gene duplication test, for clinical prediction of CYP2D6 capacity Three novel variants of known CYP2D6 alleles were discovered: *1C (T1957C), *2B (additional C2558T), and *4E (additional C2938T) Analysis of variance showed significant differences in enzymatic activity measured by the dextromethorphan metabolic ratio (MR) between carriers of EM/PM (mean MR = 006) and IM/PM (mean MR = 014) alleles and between carriers of one (mean MR = 009) and two (mean MR = 003) functional alleles The results of this study provide a solid basis for prediction of CYP2D6 capacity, as required in drug research and routine drug treatment

Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jps.2600680845

Noncompartmental Determination of the Steady‐State Volume of Distribution

Of about one dozen human P450 s that catalyze biotransformations of xenobiotics, CYP2D6 is one of the more important ones based on the number of its drug substrates. It shows a very high degree of interindividual variability, which is primarily due to the extensive genetic polymorphism that influences expression and function. This so-called debrisoquine/sparteine oxidation polymorphism has been extensively studied in many different populations and over 80 alleles and allele variants have been described. CYP2D6 protein and enzymatic activity is completely absent in less than 1% of Asian people and in up to 10% of Caucasians with two null alleles, which do not encode a functional P450 protein product. The resulting "poor metabolizer" (PM) phenotype is characterized by the inability to use CYP2D6-dependent metabolic pathways for drug elimination, which affect up to 20% of all clinically used drugs. The consequences are increased risk of adverse drug reactions or lack of therapeutic response. Today, genetic testing predicts the PM phenotype with over 99% certainty. At the other extreme, the "Ultrarapid Metabolizer" (UM) phenotype can be caused by alleles carrying multiple gene copies. "Intermediate Metabolizers" (IM) are severely deficient in their metabolism capacity compared to normal "Extensive Metabolizers" (EM), but in contrast to PMs they express a low amount of residual activity due to the presence of at least one partially deficient allele. Whereas the intricate genetics of the CYP2D6 polymorphism is becoming apparent at ever greater detail, applications in clinical practice are still rare. More clinical studies are needed to show where patients benefit from drug dose adjustment based on their genotype. Computational approaches are used to predict and rationalize substrate specificity and enzymatic properties of CYP2D6. Pharmacophore modeling of ligands and protein homology modeling are two complementary approaches that have been applied with some success. CYP2D6 is not only expressed in liver but also in the gut and in brain neurons, where endogenous substrates with high-turnover have been found. Whether and how brain functions may be influenced by polymorphic expression are interesting questions for the future.

Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry

Publisher Summary This chapter focuses on the effects of hypnotics and sedatives. Chlormethiazole is widely used as a hypnotic, particularly in older patients, where its rapid absorption and elimination suggest that it should be rapidly effective and have little hangover effect. It is also used in the treatment and prevention of delirium tremens when it is given orally or by intravenous infusion and should only be used for brief periods, e.g. up to one week. Abuse of sedatives only, as opposed to poly-drug abuse, may lead to neuropsychologic damage. Fifty-five patients with a history of exclusive dependence on sedatives were compared to matched controls on a battery of psychologic tests: scores on a synonyms test, which is believed to withstand intellectual impairment, were similar in the two groups but on tests of memory and verbal learning the experimental group's scores were significantly lower. Diazepam is used parenterally as a premedication and for minor surgical procedures such as dental treatment and endoscopies. Technical problems may arise at the site of injection. Triazolam is a short-acting benzodiazepine with a triazolo structure and thus rather different from the other benzodiazepines. It has been used mainly as a hypnotic, as which it has been shown to be effective both in the sleep laboratory and in patients.

Hypnotics and sedatives

The Spirit Level. Why Equality is Better for Everyone

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.

A multifactorial and growing crisis of health care systems in the developed world has affected medicine. In order to provide rational responses, some central concepts of the past, such as the definitions of health and disease, need to be updated. For this purpose physicians should initiate a new debate. As a point of departure the following definitions are proposed: Health is a dynamic state of wellbeing characterized by a physical, mental and social potential, which satisfies the demands of a life commensurate with age, culture, and personal responsibility. If the potential is insufficient to satisfy these demands the state is disease. This term includes sickness, illness, ill health, and malady. The described potential is divided into a biologically given and a personally acquired partial potential. Their proportions vary throughout the life cycle. The proposed definitions render it empirically possible to diagnose persons as healthy or diseased and to apportion some of the responsibility for their state of health to individuals themselves. Treatment strategies should always consider three therapeutic routes: improvements of the biologically given and of the personally acquired partial potentials and adaptations of the demands of life. These consequences favourably contrast with those resulting from the WHO-definition of health.

/pdf/towards-a-dynamic-definition-of-health-and-disease-92ohhwz5dd.pdf

Towards a Dynamic Definition of Health and Disease

The Millennium Development Goals (MDGs) mobilized global commitments to promote health, socioeconomic, and sustainable development. Trends indicate that the health MDGs may not be achieved by 2015, in part because of insufficient coordination across related health, socioeconomic, and environmental initiatives. Explicitly acknowledging the need for such collaboration, the Meikirch Model of Health posits that: Health is a state of wellbeing emergent from conducive interactions between individuals' potentials, life's demands, and social and environmental determinants. Health results throughout the life course when individuals' potentials – and social and environmental determinants – suffice to respond satisfactorily to the demands of life. Life's demands can be physiological, psychosocial, or environmental, and vary across contexts, but in every case unsatisfactory responses lead to disease. This conceptualization of the integrative nature of health could contribute to ongoing efforts to strengthen cooperation across actors and sectors to improve individual and population health – leading up to 2015 and beyond.

/pdf/defining-health-by-addressing-individual-social-and-5p6aepntta.pdf

Defining health by addressing individual, social, and environmental determinants: New opportunities for health care and public health

The method of measuring the rate of aminopyrine demethylation by breath analysis was assessed in 23 normal subjects and 20 patients with cirrhosis. Carbon 14 aminopyrine specifically labeled at the two N-methyl groups was administered by mouth in a dose of 9 mg/kg, including a total radioactivity of 2 muCi. The decay of the specific activity of 14CO2 in breath (kb) was found to correlate (r = 0.91) with the disappearance of aminopyrine from plasma (KP). In normal volunteers, kb was 22.4%/hr; in patients with alcoholic and nonalcoholic cirrhosis it was depressed to 8.4%/hr (p less than 0.001). The degree of functional impairment found with the breath test was similar to the sulfobromophthalein (BSP) disappearance curve and the galactose elimination capacity. Although many questions relating to the aminopyrine breath test remain open, our data confirm and extend previous studies of 14CO2 breath analysis after 14C-aminopyrine administration. It is concluded that it represents a simple and noninvasive procedure which quantitatively reflects the microsomal function of the cirrhotic liver.

Aminopyrine demethylation measured by breath analysis in cirrhosis.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840070403

Johannes Bircher

Papers

Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation.

Towards a Dynamic Definition of Health and Disease

Defining health by addressing individual, social, and environmental determinants: New opportunities for health care and public health

Aminopyrine demethylation measured by breath analysis in cirrhosis.

Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam.