Differences in Drug Metabolism

What is the underlying cause for these interspecies differences For equal doses, differences in plasma AUC values simply indicate differences in total body clearance. Renal and metabolic elimination processes are the major contributors to total body clearance. When allometric scaling is used as described in Chapter 30, renal clearance tends to exhibit only small differences across species, whereas there are many examples of interspecies differences in metabolism. Further, across many drug categories, metabolism is quantitatively more important than is renal elimination. Therefore, more emphasis on inter species differences in drug metabolism could improve Phase I studies. The next two sections provide specific examples of the impact of monitoring metabolism during early human studies. 

The data in Table 31.1 for iododeoxydoxorubicin (I-Dox) were obtained during first-in-human studies conducted by Gianni et al. (8). There was greater exposure to the parent drug in mice, and to the hydrox-ylated metabolite (I-Dox-ol) in humans. Overall, there was a 50-fold difference in the relative AUC exposure ratios (metabolite parent drug) for humans and 

FIGURE 31.3 Survey of acute toxicity of anticancer drugs in humans versus mice. Comparisons based upon dose (left panel) exhibit more scatter tlian do those based on drug exposure (AUC) (right panel). 

TABLE 31.1 AUC Values in Plasma for lododeoxydoxorubicin (I-Dox) and Its Metabolite (I-Dox-ol) in Mouse and Human Equitoxic Doses  

Data from Gianni h et al.] Natl Cancer Inst 1990 82 469—77. 

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Branch, R. A., Salih, S. Y. el al. (1978). Racial differences in drug metabolizing ability a study with antipyrine in the Sudan. Clin. Pharmacol. Ther., 24(3), 283-6. 

Lou, Y.C. (1990). Differences in drug metabolism polymorphism between Orientals and Caucasians. DrugMetab. Rev., 22, 451-75. 

Solute uptake can also be evaluated in isolated cell suspensions, cell mono-layers, and enterocyte membrane vesicles. In these preparations, uptake is normalized by enzyme activity and/or protein concentration. While the isolation of cells in suspension preparations is an experimentally easy procedure, disruption of cell monolayers causes dedifferentiation and mucosal-to-serosal polarity is lost. While cell monolayers from culture have become a popular drug absorption screening tool, differences in drug metabolism and carrier-mediated absorption [70], export, and paracellular transport may be cell-type- and condition-depen-dent. 

Inter-ethnic differences in drug metabolism have become a trendy, and often quite exciting, line of enquiry. Results have often been quite surprising. For... 

These are a few illustrations of the emerging pattern of inter-ethnic differences in drug metabolism, which is genetically determined. 

Sizer AR, Long SK, Roberts MHT A modulatory function of 5-hydroxytryptamine in the central nervous system, in Serotonin, CNS Receptors and Brain Function (Advances in the Biosciences, Vol 85). Edited by Bradley PB, Handley SL, Cooper SJ, et al. Oxford, England, Pergamon, 1992, pp 135-146 Skett P Biochemical basis of sex differences in drug metabolism. Pharmacol TTier 38 269-304, 1988... 

The investigators used DNA in Uver samples from diverse individuals to identify the most common single nucleotide polymorphisms in the CYP3A family of genes. They then looked for associations between the SNPs and differences in drug metabolism and clearance of the anesthetic midazolam by these individuals. They... 

Increased susceptibility to the pharmacologic or toxic activity of drugs has been reported in very young and very old patients compared with young adults (see Chapters 59 and 60). Although this may reflect differences in absorption, distribution, and elimination, differences in drug metabolism also play a role. Slower metabolism could be due to reduced activity of metabolic enzymes or reduced availability of essential endogenous cofactors. 

Caldwell J. The current status of attempts to predict species differences in drug metabolism. Drug Metab... 

The deficiency of debrisoquine metabolism (19) was also tested in our laboratory, and we found a different metabolic ratio between Chinese and Caucasian students (34). These observations, together with the old G6PD and NAT2 data and some additional comparisons, firmly planted in my mind the idea that differences in drug metabolism are not only a matter of individuals but frequently occur also between the human populations. I published a review article that probably was the first exclusively concerned with interethnic differences of drug metabolism (35). Knowledge of such differences has become very important for the pharmaceutical industry. 

Kalow W, Otton SV, Kadar D, Endrenyi L, Inaba T. Ethnic difference in drug metabolism debrisoquine 4-hydroxylation in Caucasians and Orientals. Can J Physiol Pharmacol 1980 58 1142-1144. 

Kalow W. Ethnic differences in drug metabolism. Clin Pharmacokinet 1982 7 373 100. 

In some cases, biological reasons for ethnic differences in drug-metabolizing capacity have been established, but usually they are not understood. 

Nebert, D.W. Clinical pharmacology Possible clinical importance of genetic differences in drug metabolism. Brit. Med. J. 283 537-542, 1981. 

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