Original article
Organ weights and blood flows of sheep and pig for physiological pharmacokinetic modelling

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Abstract

Introduction

Physiological approaches to pharmacokinetic analysis require data on organ sizes and organ blood flows for a given species. An internally consistent compilation of these data for sheep and pigs is needed. Furthermore, it is desirable to be able to appropriately scale these data for individuals of different sizes to simulate hypothetical populations of sheep or pigs for pharmacokinetic/pharmacodynamic modelling. Method: The literature was reviewed and tables of organ size (as a ratio of body weight) and organ perfusion (flow in ml/min per 100 g of tissue) were compiled for sheep and pigs of a standard size. Equivalent data for man were compiled using the P3M program for comparison. The standard size for sheep, pig and man were 45, 25 and 69 kg, respectively. Allometric scaling was used to modify the standard size data for body size, and the equations for doing so were coded in a small computer program. This program was tested by comparison with published sheep data (body weights 5–55.5 kg). Results: The three species differed mostly in the percentage of cardiac output going to the liver (47% for the sheep, 31% for the pig, 23% for man). The distribution of body weight in sheep could be simulated by assuming a log-normal distribution (mean 45 kg, log SD 0.12), with the ratio of organ size to body weight being normally distributed with a coefficient of variation of 8%. The distribution of cardiac output could be simulated by assuming that organ perfusion varied around the standard size value with a coefficient of variation of 35% and an allometric scaling coefficient of 0.75. Conclusion: The compiled data and code are suitable for physiological pharmacokinetic/pharmacodynamic modelling of data collected using sheep and pigs.

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:Y=aWborlog(Y)=a+Wlog(b)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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