Journal of Pharmacological and Toxicological Methods
Original articleOrgan weights and blood flows of sheep and pig for physiological pharmacokinetic modelling
Introduction
There has been an increasing interest in using pharmacokinetic models with a physiological basis. These models range from “full” physiological models with descriptions of kinetics in all the major organs (Davis and Mapleson, 1993, Poulin and Theil, 2002a, Poulin and Theil, 2002b, Rodgers et al., 2005), to recirculatory models where one or two key organs are represented with the remaining organs pooled into lumped compartments (Krejcie et al., 1994, Kuipers et al., 1999, Liu et al., 2005, Upton and Ludbrook, 2005). One of the problems confounding either of these physiological approaches is a lack of information on the size of organs and organ blood flow in various experimental animals. While data for humans and rats, and to lesser extent mice, dogs and monkeys have been tabulated (Brown et al., 1997, Clewell and Clewell, 2008), there remains a lack of information for some of the larger animals sometimes used in preclinical drug studies such as the sheep and the pig (Clewell & Clewell, 2008). The first aim of this paper is to critically compile this physiological information for the sheep and pig. Data for man are presented in the same format for comparison. A second aim is to present equations that use allometric scaling to adjust the organ volume and flow values for adult animals of different sizes. The equations were incorporated into computer code so that physiological values for populations of animals could be simulated. The equations were tested by comparison with cardiac output and body weight data from published studies in sheep.
The data were compiled from an extensive review of the literature. As a general principle, evidence from at least two sources were used to support the choice of a physiological value if possible. Data were converted to a common format (e.g. perfusion in ml/min per 100 g of tissue) and scaled for body weight if necessary. There was also a general requirement that the values chosen for the standard sheep and pig were internally consistent. This required some empirical adjustment of values so that the total body weight (the sum of all organ weights) and cardiac output (the sum of all organ blood flows) matched expected values.
Section snippets
Principles of allometric scaling
Allometry is the study of how biological variables scale with changes in body size. Studies of animals of a range of body sizes have revealed that most biological variables (Y) scale with body weight (W) according to the general equation:where a is an intercept term, and b is a slope term called the allometric coefficient. This has a characteristic value depending on the nature of Y. An allometric coefficient of 1 means that the variable is in direct proportion to body
Standard values
The compiled physiological values for a standard sheep, pigs and man are summarised in Table 1, Table 2, Table 3, respectively. Each table has references supporting the choice of values.
Simulating populations
It was found that the distribution of body weight in the Upton and Parsons data could be approximated (Fig. 1) by assuming a log-normal distribution of body weight (mean 42 kg, logSD 0.12) and by assuming that the ratio of organ weight to body weight within a sheep were normally distributed around the means for
Discussion
The concept of a “standard” size is useful when making general inferences about the physiology or pharmacology of a particular species. It has its origin in the “Reference man” developed in radiation research in the 1970's. While no individual animal may have values exactly the same as the standard animal, it would be expected that if a value was measured in enough individuals the mean value would be close to that of the standard animal. Allometric scaling provides a useful addition to the
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