Environmental factors pharmacokinetics

When considering the Hkely pharmacokinetic profile of a novel compound in man, it is important to recognize the variability that may be encountered in the cHnical setting. Animal pharmacokinetic studies are generally conducted in inbred animal colonies that tend to show minimal inter-subject variabiHty. The human population contains a diverse genetic mix, without the additional variability introduced by age, disease states, environmental factors and co-medications. Hence any estimate of pharmacokinetic behaviour in man must be tempered by the expected inherent variability. For compounds with high metabolic clearance (e. g. midazolam), inter-individual variability in metabolic clearance can lead to greater than 10-fold variation in oral clearance and hence systemic exposure [1]. 

As mentioned in two critical reviews on transcultural psychopharmacology of the TCAs (Pi et al. 1993a Sramek and Pi 1999), the concept of differences between Asian and non-Asian populations in the pharmacokinetics and pharmacodynamics of TCAs has gained support from clinical reports and controlled studies. Whether these differences are due to ethnicity, pharmacokinetics, pharmacodynamics, environmental factors, or shortcomings of study design (such as small sample size) is not definitely known. Although recent studies of CYP polymorphism support the possibility of genetic differences, future studies will need to address these issues. 

Yoon Y, Chun H, Kim E, Shon J, Bae K, et al. 2002. Genetic and environmental factors influencing on the disposition of digoxin a population pharmacokinetic approach. Clin. Pharmacol. Ther. 71 P73 (Abstr.)... 

DOLLERY, C.T., FRASER, H.S., MUCKLOW, J.C. and BULPITT, C.J. (1979) Contribution of environmental factors to variability in human drug metabolism. Drug Metab. Rev., 9, 207. KRISHNASWAMY, K. (1983) Drug metabolism and pharmacokinetics in malnutrition. TIPS, 4, 295. 

In addition to host and environmental factors, an understanding of the various properties of antibiotic classes and recognition of the more common mechanisms of resistance will provide added insight into the complex interplay between the host and microbe. Integration of pharmacokinetic and pharmacodynamic properties into microbiological data may improve antibiotic choice and, thereby, enhance the patient s prospects for recovery. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

The permeability, P (P = Pc x D), of a nonpolar substance through a cell membrane is dependent on two physicochemical factors (1) solubility in the membrane (Pc), which can be expressed as a partition coefficient of the drug between the aqueous phase and membrane phase, and (2) diffusivity or diffusion coefficient (D), which is a measure of mobility of the drug molecules within the lipid. The latter may vary only slightly among toxicants, but the former is more important. Lipid solubility is therefore one of the most important determinants of the pharmacokinetic characteristics of a chemical, and it is important to determine whether a toxicants is readily ionized or not influenced by pH of the environment. If the toxicant is readily ionized, then one needs to understand its chemicals behavior in various environmental matrices in order to adequately assess its transport mechanism across membranes. 

Figure 5.12 The principle of tiering in risk assessment simple questions can be answered by simple methods that yield conservative answers, and more complex questions require more sophisticated methods, more data, and more accurate risk predictions. PEC = Predicted Environmental Concentration, PNEC = Predicted No Effect Concentration, HI = Hazard Index, CA = Concentration Addition, RA = Response Addition, TEF = Toxicity Equivalency Factor, RPF = Relative Potency Factor, MOA = Mode of Action, PBPK = Physiologically Based Pharmacokinetic, BRN = Biochemical Reaction Network.

It seeks to explain variability by identifying factors of demographic, pathophysiological, environmental, or drug-related origin that may influence the pharmacokinetic behavior of a drug. 

Sudanese living in their home villages compared to Sudanese living in Great Britain or to Caucasians living in Great Britain. Therefore, differences in the rate of the metabolism of a drug, a pharmacokinetic factor, seem to be based in environmental differences. 

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