Influence of erythrocytes on the hepatic distribution kinetics of urea and thiourea

Şahin, Selma; Rowland, Malcolm

doi:10.1016/j.ejps.2007.03.007

Cited by 3 publications

(4 citation statements)

References 34 publications

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“…Therefore, such substances will not be removed from erythrocytes to a significant extent during single passage through the liver, effectively resulting in a red blood cell carriage effect. The presence of red blood cells may have significant effect on the hepatic distribution and elimination of such compounds (Sahin and Rowland 2007). One implication of the RBC distribution kinetics concerns the influence of route of administration on hepatic extraction of compounds.…”

Section: Discussionmentioning

confidence: 99%

“…human) in the in situ perfused rat liver preparations because of the immune response associated with the foreign cells (Karabey and Sahin 2006a). Recently, Sahin and Rowland (2007) demonstrated that some thiourea fraction is retained by the erythrocytes on transit through the liver by addition of these cells to the administered dose only. This is due to the fact that thiourea equilibrates relatively slowly between erythrocytes membrane and plasma water with a half life in the range of 2-3 min which is much slower than the approximately 10 s transit time of erythrocytes in the liver (Sahin and Rowland 2000).…”

Section: Discussionmentioning

confidence: 99%

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Investigation of distribution and elimination of terbutaline sulfate in the perfused rat liver preparation

Şahin

2010

Eur J Drug Metab Pharmacokinet

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Hepatic distribution and elimination of terbutaline sulfate (TBS) was investigated in the in situ isolated perfused rat liver preparation. Perfusion experiments were conducted using Krebs bicarbonate buffer delivered via the portal vein in a single-pass mode at a total flow rate of 15 mL min(-1). TBS was administered as a bolus (2 mg mL(-1)) in the absence and presence of erythrocytes (50% hematocrit) or albumin (1%). Immediately after a bolus administration, the outflow perfusate was collected and then concentration of TBS was determined by a validated HPLC method. Regardless of the condition, the extraction of TBS (0.35-0.51) across the liver during single pass was intermediate. Although protein binding of TBS was very low (2.5%), it was taken up slowly and continuously by erythrocytes. A blood to plasma concentration ratio of 2.8 obtained at the end of incubation period clearly indicates that TBS has an affinity to erythrocytes. However, under the conditions used in this study, hepatic distribution and elimination of TBS were not influenced by the presence of erythrocytes or albumin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Investigation of distribution and elimination of terbutaline sulfate in the perfused rat liver preparation

Şahin

2010

Eur J Drug Metab Pharmacokinet

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“…In situ liver perfusion technique developed by Miller et al. in 1951 is a well‐known dynamic model that allows simultaneous collection of perfusate, bile, and tissue samples to study hepatic absorption, metabolism, intracellular, and intercellular communication (Godoy et al., 2013; Sahin, 2003; Sahin & Karabey, 2010; Sahin & Rowland, 1998, 2004, 2007, 2013).…”

Section: Evaluation Of Tddismentioning

confidence: 99%

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

Izat

Şahin

2021

Biopharm & Drug Disp

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Transporter‐mediated drug–drug interactions are one of the major mechanisms in pharmacokinetic‐based drug interactions and correspondingly affecting drugs' safety and efficacy. Regulatory bodies underlined the importance of the evaluation of transporter‐mediated interactions as a part of the drug development process. The liver is responsible for the elimination of a wide range of endogenous and exogenous compounds via metabolism and biliary excretion. Therefore, hepatic uptake transporters, expressed on the sinusoidal membranes of hepatocytes, and efflux transporters mediating the transport from hepatocytes to the bile are determinant factors for pharmacokinetics of drugs, and hence, drug–drug interactions. In parallel with the growing research interest in this area, regulatory guidances have been updated with detailed assay models and criteria. According to well‐established preclinical results, observed or expected hepatic transporter‐mediated drug–drug interactions can be taken into account for clinical studies. In this paper, various methods including in vitro, in situ, in vivo, in silico approaches, and combinational concepts and several clinical studies on the assessment of transporter‐mediated drug–drug interactions were reviewed. Informative and effective evaluation by preclinical tools together with the integration of pharmacokinetic modeling and simulation can reduce unexpected clinical outcomes and enhance the success rate in drug development.

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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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Influence of erythrocytes on the hepatic distribution kinetics of urea and thiourea

Cited by 3 publications

References 34 publications

Investigation of distribution and elimination of terbutaline sulfate in the perfused rat liver preparation

Investigation of distribution and elimination of terbutaline sulfate in the perfused rat liver preparation

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

Drug structure–transport relationships

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