A lung perfusion preparation for the study of drug metabolism

Rosenbloom, P. M.; Bass, Allan D.

doi:10.1152/jappl.1970.29.1.138

Cited by 29 publications

(7 citation statements)

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“…Since this is the first time that lung slices have been used to study the uptake of a drug, it is not possible to compare the results obtained in the present investigation with other studies. Most other studies have been conducted on isolated lungs of rabbits or rats that were perfused either with artificial media with or without added constituents of blood or with whole blood (Alabaster & Bakhle, 1970;Rosenbloom & Bass, 1970;Junod, 1972a, b;Iwasawa, Gillis & Aghajanian, 1973;Orton, Anderson, Pickett, Eling & Fouts, 1973). The development of oedema has been the most common difficulty encountered in perfusion experiments using artificial media.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of (±)‐methadone Uptake by Rat Lung

Chi

Dixit

1977

British J Pharmacology

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1By use of a sensitive and specific fluorescence assay procedure it was shown that after subcutaneous administration to rats, (±)rmethadone was concentrated in the lung. Lung to serum ratios ranging from 25 to 60 were obtained indicating that the rat lung tissue was capable of extracting (±)-methadone against a concentration gradient.2 This phenomenon was investigated in vitro with rat lung slices incubated in Krebs-Ringer phosphate buffer (pH 7.4). The uptake was expressed in terms of tissue to medium concentration ratios (T/M ratio).3 The principal observations were: (i) Studies on the time-course of the uptake showed that the T/M ratios of (±)-methadone increased rapidly during the first 60 min of incubation and then more slowly, with a plateau occurring at 180 min; (ii) The T/M ratio of (±)-methadone progressively increased from 9.5 to 17 as the pH of the incubation medium was varied from 6.2 to 7.8; (iii) When the concentration of (±)rmethadone in the incubation medium was varied from 0.005 to 0.5 mm, the T/M ratio decreased rapidly suggesting self-saturation of the transport process. Beyond the medium concentration of 0.5 mM, the T/M ratio declined very slowly. 4 These results suggested that at low concentrations, (±)-methadone was transported predominantly by a self-saturable process while at higher concentrations it was transported by a process of simple diffusion. 5 At low concentrations (0.01 mM) the uptake of (+)-methadone was higher than that of (-)-isomer indicating stereo-specificity of the uptake process. The uptake of (±)-methadone at low concentration (0.01 mM) was significantly inhibited by low temperature, lack of 02, lack of glucose, lack of Na+ in

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Section: Discussionmentioning

confidence: 99%

“…(Alabaster & Bakhle, 1970;Rosenbloom & Bass, 1970;Junod, 1972a, b;Iwasawa, Gillis & Aghajanian, 1973;Orton, Anderson, Pickett, Eling & Fouts, 1973). The development of oedema has been the most common difficulty encountered in perfusion experiments using artificial media.…”

Section: Effect Oflack Ofglucosementioning

confidence: 99%

Characterization of (±)‐methadone Uptake by Rat Lung

Chi

Dixit

1977

British J Pharmacology

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“…A more useful in vitro preparation for studying lung kinetics is the isolated perfused lung preparation. 50,51 Kinetics are generally deduced from the efferent concentrations with pulse administration of a drug in a non-recirculating system or from concentration differences between afferent and efferent perfusate in a recirculatory system. Potential deviations from in vivo that may influence kinetic parameters include lower than normal flow rates and the use of buffer rather than blood for perfusate.…”

Section: In Vitromentioning

confidence: 99%

Kinetic Aspects of Drug Disposition in the Lungs

Upton

Doolette

1999

Clin Exp Pharma Physio

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1. The pharmacokinetic role of the lungs has been extensively studied using in vitro preparations, but this information has not been well integrated into many systemic pharmacokinetic models. 2. The lung is characterized by short diffusion distances, extremely high relative perfusion and heterogeneous cell types. Anionic and neutral lipophilic drugs have relatively small distribution volumes in the lungs due to their low lipid content. Cationic lipophilic drugs can accumulate in the lungs, probably due to trapping in mitochondria and lysosomes, forming very slowly eluting pools. 3. Drug metabolism in the lungs is possible, but not universal. The lung, generally, has a low activity for many of the metabolic enzymes found in the liver, although this activity is relatively more inducible. The resultant drug extraction would be ‘enzyme limited’, variable and flow dependent. 4. Double indicator studies of first‐pass lung kinetics can characterize short‐term distribution in the lungs, but not longer‐term distribution or metabolism; the converse applies for studies of drug concentration gradients across the lungs. No single study or model has adequately defined the short‐ and long‐term kinetics of drugs in the lungs. 5. Drug clearance in the lungs can contribute to an apparent total body clearance in excess of hepatic blood flow and cardiac output. The lung is a first pass filter for any drug administered on the venous side of the circulation and can act as a ‘capacitor’ that damps the first‐pass concentration peak in the blood after intravenous bolus injection.

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“…We chose to study metabolizing systems in rabbit lung since this animal has high levels of several "drug metabolizing enzymes" in its lung, and the mass of tissue per animal made it more likely that we could study systems in individual animals (1). There was also a system to study drug metabolism in an isolated perfused lung (2).…”

Section: Extrahepatic Toxication-detoxication Systemsmentioning

confidence: 99%

Some Studies and Comments on Hepatic and Extrahepatic Microsomal Toxication-Detoxication Systems: A Limited Discussion of Some of the Heterogeneities of These Systems and of Their Responses to Stimulation of Enzyme "Induction"

Fouts¹

1972

Environmental Health Perspectives

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A lung perfusion preparation for the study of drug metabolism

Cited by 29 publications

References 0 publications

Characterization of (±)‐methadone Uptake by Rat Lung

Characterization of (±)‐methadone Uptake by Rat Lung

Kinetic Aspects of Drug Disposition in the Lungs

Some Studies and Comments on Hepatic and Extrahepatic Microsomal Toxication-Detoxication Systems: A Limited Discussion of Some of the Heterogeneities of These Systems and of Their Responses to Stimulation of Enzyme "Induction"

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