Variability interindividual

Lampen, A., Christians, U., Guengerich, F. P., Watkins, P. B., Koiars, J. C., Bader, A., Dralle, H., Hackbarth, I., Sewing, K. F., Metabolism of the immunosuppressant tacrolimus in the small intestine cytochrome P450 drug interactions, and interindividual variability, Drug Metab. Disp. 1995, 23, 1315-1324. 

Labroo, R. B., Paine, M. F., Thummel, K. E., Kharasch, E. D., Fentanyl metabolism by human hepatic and intestinal cytochrome P4503A4. Implications for interindividual variability in disposition, efficacy and drug interactions, Drug Metab. Disp. 1997, 25, 1072-1080. 

A decrease in the efficiency of the Na+-Li+ countertransport is also observed as a direct result of Li+ administration, with a 50% inhibition in the efflux of Li+ from the erythrocytes of people on Li+ therapy [63], This decrease in activity occurs 2-4 days after commencing therapy and maximum reduction appears within 7 days the rate of transport returns to normal soon after the Li+ administration is ceased. This Li+-induced change has been attributed to a decrease in the affinity of the transporter for Li+ as the /sTmfor the process increases threefold, whereas Vmaxremains constant, in contrast to the interindividual variability [69]. 

Subject variability High intraindividual variability in QTc values (circadian and seasonal variation law of regression to the mean) High interindividual variability in QTc values (males versus females) Unknown prevalence in the general population of subjects carrying silent mutations in the ion channels responsible for cardiac repolarization (these subjects have normal QTc value but reduced repolarization reserve) Variability in the individual metabolic capacity for a given drug... 

Becquemont, L., Verstuyft, C. and Jaillon, P. (2006) Pharmacogenetics and interindividual variability in drug response cytochrome P-450 2C9 and coumarin anticoagulants. Bulletin de I Academie Nationale de Medecine, 190 (1), 37-49. discussion 50-3. 

Lin, J.H. and Lu, A.Y. (2001) Interindividual variability in inhibition and induction of cytochrome P450 enzymes. Annual Review of Pharmacology and Toxicology, 41, 535—567. 

Seaton MJ, Schlosser PM, Medinsky MA. 1995. In vitro conjugation of benzene metabolites by human liver Potential influence of interindividual variability on benzene toxicity. Carcinogenesis 16 1519-1527. 

Shiraga, T., Niwa, T., Ohno, Y. and Kagayama, A., Interindividual variability in 2-hydroxylation, 3-sulfation, and 3-glucuronidation of ethynylestradiol in human liver. Biol. Pharm. Bull., 2004, 27, 1900. 

Table 4.3 provides examples of transporter polymorphisms that have had an effect on certain substrates in vitro or in vivo that have explained interindividual variability toward these drugs in clinical pharmacology or have not. It should be mentioned that just because a polymorphism has no effect on a substrate drug in the clinic, a potential gene-drug interaction could not be found following treatment with another substrate drug. 

Over the past 20 years there has been widespread interest in monitoring plasma antidepressant, particularly tricyclic, levels to optimize the response to treatment. One aspect of this research that is universally agreed upon concerns the extensive interindividual variability among patients, but it is still uncertain whether a knowledge of the plasma drug concentration is of clinical value. 

Large interindividual variability in plasma concentrations which reflect genetically determined metabolic differences. 

The interindividual variability reflects differences in the extent of exposure, in toxicokinetics as well as in toxicodynamics. The variability due to factors which influence the extent of exposure (physiological differences in the intake, e.g., inhalation rates) can be considered by means of suitable parameters for the internal exposure (absorbed dose, area under the curve AUC, plasma concentration) if sufficient information is available. With respect to toxicokinetic factors, interindi-vidual differences in the metabolism of chemicals are generally considered as the most significant explanatory factor. Hardly any knowledge is available with respect to the factors that influence toxicodynamics. In the following, a brief overview of the factors playing a role for the toxicokinetic and toxicodynamic differences is presented. 

Humans also display marked interindividual variability in the capacity to repair damaged DNA. This variation is partly due to genetic factors, and genetic polymorphisms have been found in several proteins involved in DNA repair (Kalberlah and Schneider 1998, KEMI 2003). 

In the following text, various smdies will be described which attempt to establish a scientific rationale for the selection of the interindividual assessment factor. Based on these studies, it can be concluded that the factor for interindividual variability should preferentially be described probabilistically. However, at present there is no database-derived distribution of the interindividual factor and thus a deterministic default factor of 10, split evenly into a sub-factor of 3.16 for both toxicokinetics and for toxicodynamics, respectively, could be used to account for the inter-individual variability in the human population. Alternatively, a pathway-related UF could be applied in case the pathway(s) of the metabolism of the chemical in humans and the particular enzyme(s) are known. 

Hattis et al. (1987) examined the variability in key pharmacokinetic parameters (elimination half-lives (Ty ), area under the curve (AUC), and peak concentration (C ax) in blood) in healthy adults based on 101 data sets for 49 specific chemicals (mostly drugs). For the median chemical, a 10-fold difference in these parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, a 10-fold difference would correspond to only about 2.5 standard deviations in the population. The authors remarked that the parameters studied are only components of the overall susceptibility to toxic substances and did not include contributions from variability in exposure- and response-determining parameters. The study also implicitly excluded most human interindividual variability from age and diseases. When these other sources of variability are included, it is likely that a 10-fold difference will correspond to fewer standard deviations in the overall population and thus a greater number of people at risk of toxicity. 

Gronlund (1992) has investigated methods used for quantitative risk assessment of non-genotoxic substances, with special regard to the selection of assessment factors. Gronlund found that the 10-fold factor suggested for interindividual variability probably protects a majority but not all of the population. 

Dourson et al. (1996) considered that, in general, the default value of 10 for interindividual variability appears to be protective when starting from a median response, or by inference, from a NOAEL assumed to be from an average group of humans. When NOAELs are available in a known sensitive human subpopulation, or if human toxicokinetics or toxicodynamics are known with some certainty, this default value of 10 should be adjusted or replaced accordingly. 

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