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be difficult to quantify if extra hepatic metabolism occurs in, for example, the gut wall or kidney. |
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CL = CLH + CLGI + CLK + CLother (3) |
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Despite the difficulties of the methodology using this procedure and the many assumptions made with the calculation of both the in vitro and in vivo clearances, Houston [41] found in the published data on rats that the predictions were reasonably good. Using the incubations with microsomes, there was an overall mean overestimation of approximately 90% (median 40%), but ranged from -75 to 634% (Figure 5). Where comparative incubation methods were used in the same study, it would appear that hepatocytes gave similar predictive values to those of the microsomes, but hepatic slices gave consistently lower clearances. This is thought to be due to the inability of the drug to penetrate into the comparatively thick slices and be metabolized by all the metabolic protein present. The review by Houston [41] used data from rats, but extrapolations can similarly be made using human tissue [42,43]. However we in our lab have confirmed the findings of Houston that, for reasons not fully understood, the in vivo clearance of certain drugs may be poorly predicted, particularly those with a low clearance. |
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It is now generally well known that small animals will clear a drug or chemical faster than humans and, for this reason, the comparison of dosages to extrapolate pharmacological or toxicological studies [44] is often of little value. This is not surprising since small animals have relatively faster blood flow and larger organs than man when expressed as a percentage of body weight, and consequently clearance is more rapid and circulating levels of the administered compound are lower than could be expected in pharmacological and toxicological studies [45]. |
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However since most mammals share similar physiological and biochemical actions, these differences in physiological rates and sizes for most processes in the mammalian body have been shown to be proportional to the body weight of the animal [46] and can be related by allometry, a word from the Greek meaning the measurement (metry) of changing size (allo). It has been shown that blood flow, organ size, metabolic and respiratory rate, and many other physiological and anatomical variables are related by the general allometric equation [47]: |
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where Y is the function to be measured, W the body weight of the animal, a the coefficient, and b the exponent. For mammals, whilst a is different for each |
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