Evaluation Of Drug Metabolism Research Articles

Genetic variation and dietary response: Nutrigenetics/nutrigenomics

Advances in molecular and recombinant DNA technology have led to exquisite studies in the field of genetics and the recognition in a much more specific way, through DNA sequencing, of how unique each one of us is, and the extent to which genetic variation occurs. The importance of the effects of genetic variation has been extensively studied and applied by pharmacologists in drug development and evaluation of drug metabolism and adverse reactions to drugs. In the past two decades, physicians, geneticists, and nutritionists have begun to study the effects of genetic variation and gene−nutrient interactions in the management of chronic diseases, such as coronary heart disease, hypertension, cancer, diabetes and obesity; and the role of nutrients in gene expression. A new era is being ushered in that may be called ‘nutrigenetics/nutrigenomics’. The new genetics has enormous implications for nutrition research both in the prevention and management of chronic diseases. Because families share both genes and environment (in this case, diet), similarity may result from either. Much research has been carried out to define the contribution of each and their interaction in the development of the individual. Knowledge of genetic susceptibility to disease will help identify those at higher risk for disease, as well as their response to diet. The prospect of targeting specific dietary treatment to those predicted to gain the most therapeutic benefit clearly has important clinical and economic consequences, particularly in diseases of high prevalence such as coronary artery disease, hypertension, osteoporosis, and possibly cancer. With the unfolding genomic and technological revolution, continuing investments in research offers unprecedented opportunities to understand disease processes, prevent intrinsic and environmental risks to health and develop new approaches to improve the quality of life worldwide. Furthermore, knowledge of genetic susceptibility to disease will help identify those at higher risk for disease, as well as their response to diet. As a result, there will be a need for the development of novel foods targeted to individuals, families and subgroups within populations. Although the emphasis of new genetics has been on pharmacogenetics, it is the responsibility of the nutrition scientists to expand in parallel the relationship of genetics and nutrition and establish nutrigenetics/nutrigenomics as a major discipline in nutrition in the 21st century.

DEVELOPMENTO F DRUG METABOLISMS TUDY IN DRUG DISCOVERY

It is important to predict and evaluate drug metabolism in drug discovery, because there are many pharmacokinetic problems arising from drug metabolism. Particularly, construction of the rapid and reliable prediction. evaluation methods is important in this study. The drug metabolism items that should be investigated are raised as follows: (1) hepatic clearance, (2) metabolite profile, (3) CYP identification, (4) CYP inhibition, (5) enzyme induction. In this presentation, I will discuss the construction and application of the prediction evaluation methods for hepatic clearance, metabolic profile and CYP inhibition in drug discovery.

薬理遺伝学の発展と臨床薬理学 分子レベルから臨床医学，医薬品開発へ 酸化的薬物代謝評価のｉｎ ｖｉｔｒｏからｉｎ ｖｉｖｏへの外挿

薬理遺伝学の発展と臨床薬理学 分子レベルから臨床医学，医薬品開発へ 酸化的薬物代謝評価のｉｎ ｖｉｔｒｏからｉｎ ｖｉｖｏへの外挿

In vitro assessment of stereoselective hepatic metabolism of disopyramide in humans: Comparison with in vivo data

Metabolism of disopyramide (DP) enantiomers has been investigated in primary cultures of adult human hepatocytes. Results were compared with in vivo data obtained from a previous pharmacokinetic study (Le Corre et al. Drug Metab. Dispos. 16:858-864 1988). Metabolism of DP enantiomers as a function of incubation time showed constant velocity over time. The intracellular/extracellular distribution of both DP and mono-N-desisopropyldisopyramide did not appear to be stereoselective. Metabolism of DP enantiomers as a function of substrate concentration followed a first order kinetics. The average fractions of (-)-(R)-DP and (+)-(S)-DP metabolized in vitro (4.7 +/- 2.7 and 7.1 +/- 4.2%, respectively, n = 4) were about 5-fold lower than the fractions metabolized in vivo (26.0 +/- 6.0 and 40.2 +/- 8.8%, respectively, n = 6). The stereoselective index [(+)-(S)/(-)-(R)] of the N-dealkylation pathway obtained in vitro (1.51 +/- 0.11, n = 4) was very close to the one obtained in vivo (1.55 +/- 0.10, n = 6). These results highlight the interest of hepatocyte cultures in the evaluation of drug metabolism and especially in the assessment of stereoselectivity.

Dietary influences on the kinetics of antipyrine and aminopyrine in human subjects.

The possible dietary influences on in vivo antipyrine and aminopyrine kinetics with reference to energy (1500, 1800, 3000 kcal) and protein (5, 10, 15, 20% protein energy-PE) intake were studied in a carefully controlled metabolic experiment in young healthy adult male volunteers aged between 25-34 years. Antipyrine and aminopyrine were used to evaluate drug metabolism. On 1500 kcal intake with 10% PE, the metabolism of both aminopyrine and antipyrine were significantly reduced whereas on 1800 kcal with 10% PE intake, only aminopyrine metabolism decreased significantly as compared to 3000 kcal with 10% PE. Antipyrine clearance on 1800 kcal with 10% PE however had not decreased to the same extent as on 1500 kcal with 10% PE. The results indicate that on low calorie intake with 10% PE, the drug metabolism is decreased. When the protein intake on 1500 kcal was doubled (20% PE) there was a significant stimulation of both aminopyrine and antipyrine metabolism. Aminopyrine and antipyrine clearances on 3000 kcal with 5% PE were significantly reduced as compared to 3000 kcal with 10% and 15% PE indicating that unlike proteins, carbohydrate and/or fat calories per se do not significantly stimulate drug metabolism. When the protein energy in the diet was increased from 5% to 10% or 15% at 3000 kcal, there was a stimulation of both antipyrine and aminopyrine metabolism. Significant differences between 10% and 15% of protein energy were not observed when the energy was adequate (3000 kcal). Therefore it is necessary to consider both proteins and energy as important variables affecting drug clearances from plasma in malnourished conditions.