Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb

Heatherington, Anne C.; Rowland, Malcolm

doi:10.1007/bf02353468

Cited by 9 publications

(2 citation statements)

References 29 publications

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“…However, consistent with events shown in Fig. 8a, Anne Heatherington and Malcolm showed that intravascular distribution in the hindlimb after bolus administration can be overshadowed by events in the connecting tubing and cannulas, resulting in discrepancies between bolus and infusion pharmacokinetics [138]. Malcolm’s group has also applied the dispersion model to describe the disposition of markers and a series of barbiturates in the perfused hind leg [139].…”

Section: Pharmacokinetics In Other Perfused Organsmentioning

confidence: 85%

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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Section: Pharmacokinetics In Other Perfused Organsmentioning

confidence: 85%

Drug structure–transport relationships

Roberts

2010

J Pharmacokinet Pharmacodyn

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“…This type of anomaly has been reported previously in the perfused rat hind limb. Heatherington and Rowland [24] noted a consistent overestimation of the vascular space in the perfused hind limb by using bolus methods compared with values obtained by using whole body experiments. They suggested that transient pressure changes caused by injecting the bolus could cause additional vessels to be recruited.…”

Section: Discussionmentioning

confidence: 99%

Wash-In Methodology and Modeling to Determine Hepatocellular D-Glucose Transport in the Perfused Rat Liver

Couteur

Yin

McLean

et al. 2004

JJP

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analyzing gaseous substrates. A compartmental model was found to describe the wash-in data adequately. This type of modeling assumes that the vascular and cellular compartments in the liver are well stirred and is a much simpler interpretation of liver physiology than the distributed and dispersion models that have been used to analyze multiple indicator-dilution experiments. Carbon monoxide disposition in the liver has not previously been reported; therefore we wished to explore the modeling of wash-in experiments by using a substrate whose disposition has been elucidated in the liver by means of other techniques. In this study, wash-in experiments were used to examine the disposition of D-glucose in the perfused rat liver. Several types of physiological models were used to analyze the data, and results were compared with those reported for other methods. The disposition of substrates in the liver has been studied extensively with the multiple indicator-dilution technique. This involves the injection of a bolus of indicators into the inflow of an organ and an analysis of outflow time-activity curves. The physiological modeling of this technique is well described and include the distributed models developed by Goresky and co-workers [1-3], the dispersion model [4, 5], and the Crone-Renkin early extraction model [6, 7]. By contrast, wash-in experiments have been studied infrequently, and this technique is less well characterized. Recently, we reported the use of wash-in experiments to determine the behavior of carbon monoxide in the liver [8], hind limb [9], and placenta [10]. Wash-in experiments were chosen to simplify the technical difficulties inherent in collecting and Abstract: Wash-in experiments, which may be useful for the study of the disposition of sub-strates in the liver, have not been well described. To investigate physiological models for wash-in curves, we performed experiments on the per-fused livers of male Wistar rats anesthetized with pentobarbital. Test perfusate contained 14 C-sucrose as the extracellular marker and 3 H-glucose. Liver perfusions were performed with background glucose concentrations of 5.7, 10.7, 51.2, or 108.5 mM. Outflow time-activity curves were analyzed with the use of four models. The V max and K m for the influx of glucose were 1.1 ± 0.03 µmol/s/g and 41 ± 3 mM with the Crone-Renkin early extraction model; 1.4 ± 0.04 µmol/s/g and 36 ± 3 mM with dispersion model analysis; 1.8 ± 0.1 µmol/s/g and 25 ± 4 mM with the Goresky distributed model to fit differentiated wash-in curves; and 2.7 ± 0.6 µmol/s/g and 28 ± 21 mM with compartmental analysis. There was reasonable agreement between the four models, and they yielded results similar to those reported for glucose uptake in other preparations. [The Japanese Journal of Physiology 54: 421-429, 2004]

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Kinetics of propranolol uptake in muscle, skin, and fat of the isolated perfused rat hindlimb

Roberts

Weiß

2000

European Journal of Pharmaceutical Sciences

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Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb

Cited by 9 publications

References 29 publications

Drug structure–transport relationships

Drug structure–transport relationships

Wash-In Methodology and Modeling to Determine Hepatocellular D-Glucose Transport in the Perfused Rat Liver

Kinetics of propranolol uptake in muscle, skin, and fat of the isolated perfused rat hindlimb

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