A Two-compartment Dispersion Model Describes the Hepatic Outflow Profile of Diclofenac in the Presence of its Binding Protein

Evans, Allan M.; Hussein, Ziad; Rowland, Malcolm

doi:10.1111/j.2042-7158.1991.tb03463.x

Cited by 28 publications

(8 citation statements)

References 19 publications

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“…Some are small, lying in the range 0.054 to 0.13 (Burczynski et al, 1996;Ueda et al, 1997), whereas others are much larger, within the range 0.2 to 0.5 (Roberts et al, 1988;Evans et al, 1991). In the present study, D N estimates of both the common and specific arterial spaces were small (Ͻ0.25) and tended to be greater for the common (0.08 -0.23) than specific (0.05-0.12) space.…”

Section: Discussionmentioning

confidence: 99%

“…When analyzing the impulse response data, it is important to realize that the shape of the transit time distribution is determined not only by events within the liver but also by those occurring within the nonhepatic region of the experimental system (Goresky and Silverman, 1964;Luxon and Forker, 1982;Evans et al, 1991;Rowland and Evans, 1991). Apparatus dispersion is particularly important when modeling the outflow profiles of substances that have short mean transit times, such as red blood cells, albumin, and sucrose.…”

Section: Discussionmentioning

confidence: 99%

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Application of the Dispersion Model to Describe Disposition Kinetics of Markers in the Dual Perfused Rat Liver

Şahin

Rowland²

2007

Drug Metab Dispos

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ABSTRACT:The liver receives two blood supplies, portal and hepatic, yet most in situ studies use only portal perfusion. A model based on dispersion principles was developed to provide baseline data of the dual perfused rat liver preparation by characterizing the temporal outflow profiles of noneliminated reference markers (vascular marker, red blood cells; extracellular markers, albumin, sucrose; and intracellular markers, urea, water). The model consists of two components: the common and a specific arterial space operating in parallel. The common space receives all the portal flow and some of the arterial flow; the remaining arterial flow perfuses the specific space. Each space is divided into three subspaces: vascular, interstitial, and intracellular. The extent of axial spreading of solute on passage through the common and specific spaces is characterized by their respective dispersion numbers, D N . The model was fully characterized by analysis of the outflow data following independent bolus administration into the portal vein and hepatic artery. The model provided a good fit of the data for all reference compounds. The estimate of the fraction of the total space assigned to the specific arterial space varied from 4 to 11%, with a mean value of 9%. The estimated D N was always small (<0.25) and tended to be greater for the common space (0.08-0.23) than the specific space (0.05-0.12). However, for each space, there was no significant difference in the D N value among all reference markers; this is assumed to arise because all markers are reflecting a common feature, the heterogeneity of the microvasculature.Despite the liver receiving a dual blood supply, the portal vein (PV) has been the main source of input for studying hepatic disposition using the isolated perfused liver preparation. Nevertheless, this approach is unphysiological in the sense that it excludes the possible contribution from the hepatic artery (HA). Studies concerned with the interaction of these two inputs suggest that both a common and specific space exists: the majority of the sinusoids are the common channels for both streams, whereas a small fraction (approximately 5-10%; Field and Andrews, 1968;Ahmad et al., 1984;Reichen, 1988;Kassissia et al., 1994;Pang et al., 1994;Sahin and Rowland, 1998b) remains specific to the HA. Although existing clearance data suggest that the difference between the PV and HA might be attributable to the presence of the specific arterial space (Ahmad et al., 1984;Pang et al., 1994;Sahin and Rowland, 2000b), they do not provide any information on the disposition characteristics of this space. However, this can be achieved by defining each space in a model. The axial dispersion model has its origins in chemical engineering (Kreft and Zuber, 1978), where it was developed to describe the mixing of substances on transport through a packed reactor bed. It was introduced into the field of pharmacokinetics by Roberts and Rowland (1986a,b,c) to describe the mixing events in the liver. They proposed that the branch p...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Application of the Dispersion Model to Describe Disposition Kinetics of Markers in the Dual Perfused Rat Liver

Şahin

Rowland²

2007

Drug Metab Dispos

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“…This finding confirms that the dispersion number is a measure of the variation in residence times of solutes in the hepatic vasculature. In other studies, Malcolm’s group has examined hepatic disposition of salicylate [100], the effect of varying plasma [101, 102] and hepatic tissue binding [103], as well as the role of the dual liver blood supply [104] and erythrocyte binding [105] on hepatic disposition kinetics. My group’s work has taken a slightly different track and concentrated on solute structure-hepatic disposition relationships in normal and in diseased livers.…”

Section: Pharmacokinetics In the Perfused Rat Livermentioning

confidence: 99%

Drug structure–transport relationships

Roberts

2010

J Pharmacokinet Pharmacodyn

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Malcolm Rowland has greatly facilitated an understanding of drug structure–pharmacokinetic relationships using a physiological perspective. His view points, covering a wide range of activities, have impacted on my own work and on my appreciation and understanding of our science. This overview summarises some of our parallel activities, beginning with Malcolm’s work on the pH control of amphetamine excretion, his work on the disposition of aspirin and on the application of clearance concepts in describing the disposition of lidocaine. Malcolm also spent a considerable amount of time developing principles that define solute structure and transport/pharmacokinetic relationships using in situ organ studies, which he then extended to involve the whole body. Together, we developed a physiological approach to studying hepatic clearance, introducing the convection–dispersion model in which there was a spread in blood transit times through the liver accompanied by permeation into hepatocytes and removal by metabolism or excretion into the bile. With a range of colleagues, we then further developed the model and applied it to various organs in the body. One of Malcolm’s special interests was in being able to apply this knowledge, together with an understanding of physiological differences in scaling up pharmacokinetics from animals to man. The description of his many other activities, such as the development of clearance concepts, application of pharmacokinetics to the clinical situation and using pharmacokinetics to develop new compounds and delivery systems, has been left to others.

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“…In particular, the importance of catheters has been recognized in liver disposition kinetics (Evans et al, 1991), where the inverse Gaussian distribution has been used as a catheter-modeling function. A number of subsequent investigations have also used the inverse Gaussian distribution to model catheter function in this context (Evans et al, 1993;Roberts et al, 1998;Weiss et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…With catheters 1 and 2 joined together, and using a bolus injection, it is possible to recover the concentration}time pro"le, f (t), by "tting some empirical function with free parameters to the experimental points. This method is widely used (Evans et al, 1991) with the inverse Gaussian distribution g(t) chosen to approximate f (t), where…”

Section: Introductionmentioning

confidence: 99%