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• W2015983312 abstract "The lungs are pharmacologically active organs and affect the blood concentrations of drugs given intravenously. The lungs can take up, retain, metabolize and delay the release of many drugs and compounds. The ability of the lungs to remove endogenous compounds from the pulmonary arterial blood was recognized in the 1960s.112Vane JR The release and fate of vaso-active hormones in the circulation.Br J Pharmacol. 1969; 35: 209-242Crossref PubMed Scopus (445) Google Scholar The chemicals and drugs that are preferentially taken up by the lungs have diverse chemical structures and pharmacological activities. Philpot82Philpot RM Uptake, accumulation, and metabolism of chemicals by the lung.in: Bahkle YS Vane JR Metabolic Functions of the Lung. Marcel Dekker, New York1977: 123-171Google Scholar noted that compounds with significant pulmonary uptake were basic amines with pKa values >8. Although not limited to such compounds, pulmonary uptake is most relevant for drugs with these characteristics. Many of the drugs used in anaesthesia are basic amines, and the pulmonary uptake of anaesthetics has attracted the interest of anaesthetists. This review describes how the pharmacokinetic function of the lungs can be studied, which anaesthetics are taken up by the lungs, how the pharmacokinetic function of the lungs is affected and how this can be related to systemic pharmacokinetics. A further introduction to the pharmacokinetic function of the lungs is available in earlier reviews by Bend and colleagues,6Bend JR Serabjet-Singh CJ Philpot RM The pulmonary uptake, accumulation and metabolism of xenobiotics.Annu Rev Pharmacol Toxicol. 1985; 25: 97-125Crossref PubMed Google Scholar Bahkle,3Bakhle YS Pharmacokinetic and metabolic properties of lung.Br J Anaesth. 1990; 65: 79-93Crossref PubMed Scopus (31) Google Scholar and Roerig and colleagues.89Roerig DL Ahlf SB Dawson CA Linehan JH Kampine JP First pass uptake in the human lung of drugs used during anesthesia.Adv Pharmacol. 1994; 31: 531-549Crossref PubMed Scopus (12) Google Scholar In describing pulmonary uptake, several terms are used. The expression ‘pulmonary uptake’ is reserved for the process of transfer of a drug from the blood into the lungs, regardless of subsequent metabolism or release back into the blood. ‘Extraction’ is often used as a synonym of ‘uptake’. The expression ‘first-pass uptake’ is reserved for the instantaneous extraction of a drug and indicates the dynamics of the uptake processes. Thus, ‘extraction’ refers to the rate and direction of the transfer of the drug to and from the lung tissue after a bolus injection during a study of first-pass retention. When release from the lungs occurs, the extraction becomes negative. ‘Retention’ is related to the injected dose, and is expressed as the percentage of the injected dose that remains in the lungs after a given time, for instance after the first-pass period. ‘Extraction’ and ‘retention’ are typically used when the lung uptake is studied using a double-indicator dilution technique. In isolated perfused lung studies, the expressions ‘accumulation’ and ‘persistence’ are used to describe lung uptake. ‘Accumulation’ is the percentage of the studied drug retained in the lungs once equilibrium conditions have been reached, while ‘persistence’ is the percentage remaining after the lungs have been washed with a drug-free perfusate. If the drug undergoes elimination in the lungs, this process is described as ‘removal’ or ‘clearance’. Clearance is expressed as a rate (ml min−1) or a percentage decrease in the concentration in the systemic arterial blood in comparison with the concentration in the pulmonary arterial blood. Lung uptake can be studied both in the laboratory and at the bedside. The methods of investigation fall into three groups: in vitro methods, perfused lung models and in vivo methods.118Woods HF Meredith A Tucker GT Shortland JR Methods for the study of lung metabolism.Ciba Found Symp. 1980; 78: 61-83PubMed Google Scholartable 1 gives an overview of the techniques. We will consider only the techniques that are used clinically and in intact animals.Table 1Methods for the study of lung uptake of drugsIn vitroLung slicesLung homogenatesIsolated lung cell or cultured cellsSubcellular fractionsIsolated perfused lung modelsLocation Isolated, ex vivo In situ, in vivoPerfusion type Hydrostatic or pulsatile Single-pass or recirculation Crystalloid, plasma protein or blood perfusateVentilation No ventilation Static inflation VentilatedIn vivo modelsDouble-indicator dilutionClearance rateMass balanceSystem dynamicsRecirculatory modelling Open table in a new tab In intact animals or in patients, pulmonary uptake of drugs can be studied by measuring arteriovenous differences after i.v. injection or during infusion of the drug. For drugs that undergo significant metabolic clearance in the lungs, a concentration difference will be present between the arterial and venous sides of the pulmonary circulation during steady-state conditions. On the basis of these concentration differences, the pulmonary extraction ratio can be calculated as the fraction of the cardiac output completely cleared of the test drug. This approach has been used to examine the pulmonary clearance of dopamine after cardiopulmonary bypass in cardiac surgical patients.31Hayashi Y Sumikawa K Yamatodani A Kamibayashi T Mammoto T Kuro M Quantitative analysis of pulmonary clearance of exogenous dopamine after cardiopulmonary bypass in humans.Anesth Analg. 1993; 76: 107-112PubMed Google Scholar Measurement of pulmonary clearance rate requires pulmonary arterial blood sampling, which may be difficult in some situations (e.g. studies in volunteers). Based on transpulmonary concentration gradients, lung uptake may be studied using mass balance calculations based on the law of conservation of matter.109Upton RN Mather LE Runciman WB Nancarrow C Carapetis RJ The use of mass balance principles to describe regional drug distribution and elimination.J Pharmacokinet Biopharm. 1988; 16: 13-29Crossref PubMed Scopus (44) Google Scholar Using the concentrations in the pulmonary artery and the aorta (or radial artery), both the net flux into the lungs and the mass balance can be calculated. The mass balance of a drug over time is the integral of organ blood flow and the arterial– venous concentration difference. By plotting the net flux to the lungs and the mass balance against time during and after drug administration, one can distinguish between distribution and elimination. It is relatively easy to obtain pulmonary arterial blood samples in humans, using a pulmonary artery catheter, and the blood flow through the lungs (equal to cardiac output) can be measured by thermodilution. The uptake of drugs in the lungs can be studied using this technique in patients.13Boer F Hoeft A Scholz M Bovill JG Burm AG Hak A Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis.J Pharmacokinet Biopharm. 1996; 24: 197-218Crossref PubMed Scopus (11) Google Scholar Unfortunately, the method has significant limitations, allowing only cautious interpretation of the results, and can be technically difficult as it requires very frequent sampling from the pulmonary arterial catheter. Transpulmonary concentration differences can also be analysed using system dynamics analysis.13Boer F Hoeft A Scholz M Bovill JG Burm AG Hak A Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis.J Pharmacokinet Biopharm. 1996; 24: 197-218Crossref PubMed Scopus (11) Google Scholar 111vanRossum JM de Bie JE van Lingen G Teeuwen HW Pharmacokinetics from a dynamical systems point of view.J Pharmacokinet Biopharm. 1989; 17: 365-392Crossref PubMed Scopus (37) Google Scholar This method has been used to describe the pulmonary uptake of alfentanil in pigs and the pulmonary uptake of sufentanil in patients.13Boer F Hoeft A Scholz M Bovill JG Burm AG Hak A Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis.J Pharmacokinet Biopharm. 1996; 24: 197-218Crossref PubMed Scopus (11) Google Scholar The method has received little attention because the method and the mathematical analysis required to determine the transfer function are both complex. The above methods require pulmonary arterial or mixed venous blood samples, which are technically difficult to obtain in patients if frequent samples are needed. Pulmonary arterial sampling can be omitted if another agent, which does not undergo pulmonary extraction, is given at the same time. Usually, a dye is used (e.g. indocyanine green (ICG)), and this technique is the double-indicator dilution technique. It was first used for the study of lung uptake of drugs by Geddes and colleagues27Geddes DM Nesbitt K Traill T Blackburn JP First pass uptake of 14C propranolol by the lung.Thorax. 1979; 34: 810-813Crossref PubMed Scopus (31) Google Scholar and by Jorfeldt and colleagues50Jorfeldt L Lewis DH Löfström JB Post C Lung uptake of lidocaine in healthy volunteers.Acta Anaesthesiol Scand. 1979; 23: 567-574Crossref PubMed Scopus (47) Google Scholar to study lung uptake of propranolol and lidocaine in humans. The test drug and a dye or indicator are injected together on the arterial side of the pulmonary circulation, usually into the right atrium. Injection is followed by frequent blood sampling on the venous side of the lungs, e.g. from the radial or femoral artery. The blood concentration–time curve of the indicator is the reference curve of no pulmonary uptake (Fig. 1). Because both the indicator and the test drug re-enter the pulmonary circulation after their passage through the systemic circulation, peaks from recirculation are typically observed in the descending portion of the concentration–time curves. Before the indicator concentration can be used to calculate extraction and retention, the curve must be corrected for this recirculation. By log linear extrapolation (usually log linear regression) an estimate is obtained of the indicator concentration–time curve beyond the point of recirculation (thin line in Fig. 1). The curve thus obtained is the primary curve. After dose correction, the primary curve of the indicator and the concentration–time curve of the test drug are used to calculate extraction and retention of the test drug. The double-indicator technique requires rapid sampling techniques (often sampling every 1–3 s). The method can only be applied for the first-pass period and does not indicate what happens to the test drug after this period. The method relies on the assumption of mono-exponential decay of the ICG concentration curve to construct the primary curve, and this assumption may, in some circumstances, not be valid.16Böck JC Deuflhard P Hoeft A et al.Evaluation of monoexponential extrapolation of transpulmonary thermal-dye kinetics by use of a new model-free deconvolution algorithm.Med Instrum. 1988; 22: 20-28PubMed Google Scholar Times after the first-pass period can be studied if more advanced methods are used, using recirculatory models.55Krejcie TC Avram MJ Gentry WB Niemann CU Janowski MP Henthorn TK A recirculatory model of the pulmonary uptake and pharmacokinetics of lidocaine based on analysis of arterial and mixed venous data from dogs.J Pharmacokinet Biopharm. 1997; 25: 169-190Crossref PubMed Scopus (40) Google Scholar 61Kuipers JA Boer F Olieman W Burm AG Bovill JG First-pass lung uptake and pulmonary clearance of propofol: assessment with a recirculatory indocyanine green pharmacokinetic model.Anesthesiology. 1999; 91: 1780-1787Crossref PubMed Scopus (61) Google Scholar With this technique, the indocyanine green concentrations after the first-pass period are used to construct a recirculatory pharmacokinetic model with pulmonary and peripheral compartments connected in series. Once a complete model is obtained for the indicator, the drug undergoing lung uptake can be modelled to describe its pulmonary uptake. Because the drug undergoes uptake in lung tissues, it may be necessary to include a tissue compartment in the model.61Kuipers JA Boer F Olieman W Burm AG Bovill JG First-pass lung uptake and pulmonary clearance of propofol: assessment with a recirculatory indocyanine green pharmacokinetic model.Anesthesiology. 1999; 91: 1780-1787Crossref PubMed Scopus (61) Google Scholar We will discuss this possibility later in the review. Compared with the classic double-indicator dilution technique, recirculatory modelling allows the study of lung uptake beyond the first pass period. Contrary to other methods (mass balance, systems analysis), with this method lung uptake can be modelled without the need for pulmonary arterial sampling. Many drugs undergo pulmonary uptake, but we will only discuss agents used during anaesthesia (Table 2). Propranolol is included because the β-adrenoceptor antagonists are often used by the anaesthetist and are taken up after i.v. injection. They also affect pulmonary uptake of anaesthetics and could alter the pharmacokinetics of these compounds.Table 2Drugs used in anaesthesia that can be taken up by the lungsLocal anaestheticsOpioids Lidocaine2Audi SH Dawson CA Linehan JH Krenz GS Ahlf SB Roerig DL Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung.J Appl Physiol. 1998; 84: 516-530PubMed Google Scholar 8Bertler A Lewis DH Löfström JB Post C In vivo lung uptake of lidocaine in pigs.Acta Anaesthesiol Scand. 1978; 22: 530-536Crossref PubMed Scopus (32) Google Scholar 30Hasegawa K Yukioka H Hayashi M Tatekawa S Fujimori M Lung uptake of lidocaine during hyperoxia and hypoxia in the dog.Acta Anaesthesiol Scand. 1996; 40: 489-495Crossref PubMed Scopus (4) Google Scholar 50Jorfeldt L Lewis DH Löfström JB Post C Lung uptake of lidocaine in healthy volunteers.Acta Anaesthesiol Scand. 1979; 23: 567-574Crossref PubMed Scopus (47) Google Scholar 50Jorfeldt L Lewis DH Löfström JB Post C Lung uptake of lidocaine in healthy volunteers.Acta Anaesthesiol Scand. 1979; 23: 567-574Crossref PubMed Scopus (47) Google Scholar 54Kotrly KJ Roerig DL Ahlf SB Kampine JP First pass uptake of lidocaine, diazepam and thiopental in the human lung.Anesth Analg. 1988; 67: S119Crossref Google Scholar 83Post C Studies on the pharmacokinetic function of the lung with special reference to lidocaine.Acta Pharmacol Toxicol. 1979; 44: 1-53PubMed Google Scholar 84Post C Andersson GG Ryrfeld A Nilsson E Transport and binding of lidocaine by lung slices and perfused lungs of rats.Acta Pharmacol Toxicol. 1978; 43: 156-163Crossref PubMed Scopus (40) Google Scholar Fentanyl7Bentley JB Conahan TJ Cork RC Fentanyl sequestration in lungs during cardiopulmonary bypass.Clin Pharmacol Ther. 1983; 35: 703-706Crossref Scopus (34) Google Scholar 67Matot I Neely CF Katz RY Marshall BE Fentanyl and propofol uptake by the lung: effect of time between injections.Acta Anaesthesiol Scand. 1994; 38: 711-715Crossref PubMed Scopus (19) Google Scholar 94Roerig DL Kotrly KJ Vocins E Ahlf SB Dawson CA Kampine JP First pass uptake of fentanyl, meperidine and morphine in the human lung.Anesthesiology. 1987; 67: 466-472Crossref PubMed Scopus (88) Google Scholar 106Taeger K Weninger E Schmelzer F Adt M Franke N Peter K Pulmonary kinetics of fentanyl and alfentanil in surgical patients.Br J Anaesth. 1988; 61: 425-434Crossref PubMed Scopus (45) Google Scholar 113Waters CM Avram MJ Krejcie TC Henthorn TK Uptake of fentanyl in pulmonary endothelium.J Pharmacol Exp Ther. 1999; 288: 157-163PubMed Google Scholar, 114Waters CM Krejcie TC Avram MJ Facilitated uptake of fentanyl, but not alfentanil, by human pulmonary endothelial cells.Anesthesiology. 2000; 93: 825-831Crossref PubMed Scopus (19) Google Scholar, 115Williams KS Susla G Temeck BK Piscitelli SC Pass HI Pharmacokinetics of fentanyl during hyperthermic, isolated lung perfusion.South Med J. 1998; 91: 261-265Crossref PubMed Scopus (2) Google Scholar Bupivacaine42Irestedt L Andreen M Belfrage P Fagerstroem T The elimination of bupivacaine (Marcain) after short intravenous infusion in the dog: with special reference to the role played by the liver and lungs.Acta Anaesthesiol Scand. 1978; 22: 413-422Crossref PubMed Scopus (12) Google Scholar 74Palazzo MGA Kalso EA Argiras E Madgwick R Sear JW First pass lung uptake of bupivacaine: effect of acidosis in an intact rabbit lung model.Br J Anaesth. 1991; 67: 759-763Crossref PubMed Scopus (15) Google Scholar 101Sharrock NE Mather LE Go G Sculco TP Arterial and pulmonary arterial concentrations of the enantiomers of bupivacaine after epidural injection in elderly patients.Anesth Analg. 1998; 86: 812-817Crossref PubMed Google Scholar Sufentanil11Boer F Bovill JG Burm AGL Mooren RAG Uptake of sufentanil, alfentanil and morphine in the lungs of patients about to undergo coronary artery surgery.Br J Anaesth. 1992; 68: 370-375Crossref PubMed Scopus (25) Google Scholar, 12Boer F Engbers FH Bovill JG Burm AG Hak A First-pass pulmonary retention of sufentanil at three different background blood concentrations of the opioid.Br J Anaesth. 1995; 74: 50-55Crossref PubMed Scopus (10) Google Scholar, 13Boer F Hoeft A Scholz M Bovill JG Burm AG Hak A Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis.J Pharmacokinet Biopharm. 1996; 24: 197-218Crossref PubMed Scopus (11) Google Scholar, 14Boer F Olofsen E Bovill JG et al.Pulmonary uptake of sufentanil during and after constant rate infusion.Br J Anaesth. 1996; 76: 203-208Crossref PubMed Scopus (9) Google Scholar Mepivacaine52Kietzmann D Foth H Geng WP Rathgeber J Gundert-Remy U Kettler D Transpulmonary disposition of prilocaine, mepivacaine, and bupivacaine in humans in the course of epidural anaesthesia.Acta Anaesthesiol Scand. 1995; 39: 885-890Crossref PubMed Scopus (20) Google Scholar Alfentanil2Audi SH Dawson CA Linehan JH Krenz GS Ahlf SB Roerig DL Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung.J Appl Physiol. 1998; 84: 516-530PubMed Google Scholar 11Boer F Bovill JG Burm AGL Mooren RAG Uptake of sufentanil, alfentanil and morphine in the lungs of patients about to undergo coronary artery surgery.Br J Anaesth. 1992; 68: 370-375Crossref PubMed Scopus (25) Google Scholar 13Boer F Hoeft A Scholz M Bovill JG Burm AG Hak A Pulmonary distribution of alfentanil and sufentanil studied with system dynamics analysis.J Pharmacokinet Biopharm. 1996; 24: 197-218Crossref PubMed Scopus (11) Google Scholar 106Taeger K Weninger E Schmelzer F Adt M Franke N Peter K Pulmonary kinetics of fentanyl and alfentanil in surgical patients.Br J Anaesth. 1988; 61: 425-434Crossref PubMed Scopus (45) Google Scholar Prilocaine52Kietzmann D Foth H Geng WP Rathgeber J Gundert-Remy U Kettler D Transpulmonary disposition of prilocaine, mepivacaine, and bupivacaine in humans in the course of epidural anaesthesia.Acta Anaesthesiol Scand. 1995; 39: 885-890Crossref PubMed Scopus (20) Google Scholar Pethidine80Persson MP Hartvig P Paalzow L Pulmonary disposition of pethidine in postoperative patients.Br J Clin Pharmacol. 1988; 25: 235-241Crossref PubMed Scopus (6) Google Scholar 94Roerig DL Kotrly KJ Vocins E Ahlf SB Dawson CA Kampine JP First pass uptake of fentanyl, meperidine and morphine in the human lung.Anesthesiology. 1987; 67: 466-472Crossref PubMed Scopus (88) Google ScholarAnaesthetics Methadone90Roerig DL Dahl RR Dawson CA Wang RIH Effect of plasma protein binding on the uptake of methadone and diazepam in the isolated perfused rat lung.Drug Metab Dispos. 1984; 12: 536-542PubMed Google Scholar Propofol32He YL Ueyama H Tashiro C Mashimo T Yoshiya I Pulmonary disposition of propofol in surgical patients.Anesthesiology. 2000; 93: 986-991Crossref PubMed Scopus (54) Google Scholar 61Kuipers JA Boer F Olieman W Burm AG Bovill JG First-pass lung uptake and pulmonary clearance of propofol: assessment with a recirculatory indocyanine green pharmacokinetic model.Anesthesiology. 1999; 91: 1780-1787Crossref PubMed Scopus (61) Google Scholar 67Matot I Neely CF Katz RY Marshall BE Fentanyl and propofol uptake by the lung: effect of time between injections.Acta Anaesthesiol Scand. 1994; 38: 711-715Crossref PubMed Scopus (19) Google Scholar 68Matot I Neely CF Katz RY Neufeld GR Pulmonary uptake of propofol in cats. Effect of fentanyl and halothane.Anesthesiology. 1993; 78: 1157-1165Crossref PubMed Scopus (73) Google Scholar Morphine11Boer F Bovill JG Burm AGL Mooren RAG Uptake of sufentanil, alfentanil and morphine in the lungs of patients about to undergo coronary artery surgery.Br J Anaesth. 1992; 68: 370-375Crossref PubMed Scopus (25) Google Scholar 94Roerig DL Kotrly KJ Vocins E Ahlf SB Dawson CA Kampine JP First pass uptake of fentanyl, meperidine and morphine in the human lung.Anesthesiology. 1987; 67: 466-472Crossref PubMed Scopus (88) Google Scholar Thiopental54Kotrly KJ Roerig DL Ahlf SB Kampine JP First pass uptake of lidocaine, diazepam and thiopental in the human lung.Anesth Analg. 1988; 67: S119Crossref Google Scholar Codeine2Audi SH Dawson CA Linehan JH Krenz GS Ahlf SB Roerig DL Pulmonary disposition of lipophilic amine compounds in the isolated perfused rabbit lung.J Appl Physiol. 1998; 84: 516-530PubMed Google Scholar Ketamine36Henthorn TK Krejcie TC Niemann CU Enders-Klein C Shanks CA Avram MJ Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective.Anesthesiology. 1999; 91: 1733-1743Crossref PubMed Scopus (34) Google ScholarCatecholaminesBenzodiazepines Norepinephrine35Hendriksen JH Christensen NJ Ring-Larsen H Pulmonary extraction of circulating noradrenaline in man.Eur J Clin Invest. 1986; 16: 423-427Crossref PubMed Scopus (15) Google Scholar 40Hughes J Gillis CN Bloom FE The uptake and disposition of dl-norepinephrine in perfused rat lung.J Pharmacol Exp Ther. 1969; 169: 237-248PubMed Google Scholar 64Lee R Neya K Svizzero TA Koski G Mitchell JD Vlahakes GJ Norepinephrine infusion following cardiopulmonary bypass: effect of infusion site.J Surg Res. 1995; 58: 143-148Abstract Full Text PDF PubMed Scopus (5) Google Scholar Diazepam54Kotrly KJ Roerig DL Ahlf SB Kampine JP First pass uptake of lidocaine, diazepam and thiopental in the human lung.Anesth Analg. 1988; 67: S119Crossref Google Scholar 90Roerig DL Dahl RR Dawson CA Wang RIH Effect of plasma protein binding on the uptake of methadone and diazepam in the isolated perfused rat lung.Drug Metab Dispos. 1984; 12: 536-542PubMed Google Scholar Dopamine17Bryan-Lluka LJ James KM Bonisch H Porzgen P Guice KS Oldham KT Catecholamine uptake and metabolism in rat lungs.Adv Pharmacol. 1998; 42: 353-356Crossref PubMed Scopus (4) Google Scholar 18Bryan-Lluka LJ Westwood NN O'Donnell SR Vascular uptake of catecholamines in perfused lungs of the rat occurs by the same process as Uptake-1 in noradrenergic neurones.Naunyn Schmiedebergs Arch Pharmacol. 1992; 345: 319-326Crossref PubMed Scopus (36) Google Scholar 98Russell WJ Frewin DB Jonsson JR Pulmonary extraction of catecholamines in critically ill patients.Anaesth Intensive Care. 1982; 10: 319-323PubMed Google Scholar 103Sole MJ Drobac M Schwartz L Hussain MN Vaughan-Neil EF The extraction of circulating catecholamines by the lungs in normal man and in patients with pulmonary hypertension.Circulation. 1979; 60: 160-163Crossref PubMed Scopus (86) Google Scholar 105Sumikawa K Hayashi Y Yamatodami A Yoshiya I Contribution of the lungs to the clearance of exogenous dopamine in humans.Anesth Analg. 1991; 72: 622-626Crossref PubMed Scopus (10) Google Scholarβ-Adrenoceptor blockers Propranolol22Dargent F Neidhart P Bachmann M Suter PM Junod AF Simultaneous measurement of serotonin and propranolol pulmonary extraction in patients after extracorporeal circulation and surgery.Am Rev Respir Dis. 1985; 131: 242-245PubMed Google Scholar 38Howell RE Lanken PN Pulmonary accumulation of propranolol in vivo: sites and physiochemical mechanism.J Pharmacol Exp Ther. 1992; 263: 130-135PubMed Google Scholar 39Howell RE Lanken PN Hansen-Flaschen JH Haselton FR Albelda SM Fishman AP Pulmonary extraction of propanolol in normal and oxygen-toxic sheep.J Pharmacol Exp Ther. 1989; 250: 93-99PubMed Google Scholar 45Iwamoto K Watanabe J Aoyama Y High capacity for pulmonary first-pass elimination of propranolol in rats.J Pharm Pharmacol. 1987; 39: 1049-1051Crossref PubMed Scopus (15) Google Scholar 60Kronhauser DM Vestal DM Vestal RE Shand DG Uptake of propranolol by the lungs and its displacement by other drugs: involvement of the alveolar macrophage.Pharmacology. 1980; 20: 275-283Crossref PubMed Scopus (21) Google Scholar 75Pang JA Blackburn JP Butland RJA Corrin B Williams TR Geddes DM Propranolol uptake by dog lung: effect of pulmonary artery occlusion and shock lung.J Appl Physiol. 1983; 52: 393-402Google Scholar, 76Pang JA Butland RJA Brooks N Cattell M Geddes DM Impaired lung uptake of propranolol in human pulmonary emphysema.Am Rev Respir Dis. 1982; 125: 194-198PubMed Google Scholar, 77Pang JA Williams TR Blackburn JP Butland RJA Geddes DM First-pass lung uptake of propranolol enhanced in anaesthetized dogs.Br J Anaesth. 1981; 53: 601-604Crossref PubMed Scopus (7) Google Scholar Open table in a new tab The earliest works on lung uptake were on local anaesthetics such as lidocaine. In one of the first studies, the lung uptake of lidocaine was studied in anaesthetized pigs. The first-pass pulmonary uptake was 41 and 28% after injection of 0.5 and 2 mg kg−1 respectively.8Bertler A Lewis DH Löfström JB Post C In vivo lung uptake of lidocaine in pigs.Acta Anaesthesiol Scand. 1978; 22: 530-536Crossref PubMed Scopus (32) Google Scholar After two consecutive boluses of lidocaine 0.5 mg kg−1 given 10 min apart to healthy volunteers, the first-pass pulmonary retention was 60 and 55% respectively.50Jorfeldt L Lewis DH Löfström JB Post C Lung uptake of lidocaine in healthy volunteers.Acta Anaesthesiol Scand. 1979; 23: 567-574Crossref PubMed Scopus (47) Google Scholar The uptake in the lungs can be modelled using recirculatory modelling techniques.55Krejcie TC Avram MJ Gentry WB Niemann CU Janowski MP Henthorn TK A recirculatory model of the pulmonary uptake and pharmacokinetics of lidocaine based on analysis of arterial and mixed venous data from dogs.J Pharmacokinet Biopharm. 1997; 25: 169-190Crossref PubMed Scopus (40) Google Scholar Lidocaine has an apparent pulmonary tissue volume of 39 ml kg−1 in dogs, nine times greater than that of antipyrine (4.5 ml kg−1), which is an indicator for total body water. This shows that lidocaine binds extensively to the non-aqueous content of the lungs (lipids, proteins). In isolated rat lungs, the accumulation of lidocaine has a bi-exponential pattern, indicating at least two compartments available for pulmonary accumulation of lidocaine.83Post C Studies on the pharmacokinetic function of the lung with special reference to lidocaine.Acta Pharmacol Toxicol. 1979; 44: 1-53PubMed Google Scholar At clinical concentrations, uptake of lidocaine by the lung appears to be linear.30Hasegawa K Yukioka H Hayashi M Tatekawa S Fujimori M Lung uptake of lidocaine during hyperoxia and hypoxia in the dog.Acta Anaesthesiol Scand. 1996; 40: 489-495Crossref PubMed Scopus (4) Google Scholar In in vivo isolated perfused lung lobes from dogs, lung uptake was not affected by varying the concentration between 5 and 70 µg ml−1. Lung uptake decreased with time from 41–51% in the first minute to 7–12% in the tenth minute, suggesting equilibration for a given constant blood concentration. Several factors affect lung uptake of lidocaine. Lung uptake increases with pH, both in vivo and in vitro.85Post C Andersson GG Ryrfeld A Nilsson E Physio-chemical modification of lidocaine uptake in rat lung tissue.Acta Pharmacol Toxicol. 1979; 44: 103-109Crossref PubMed Scopus (28) Google Scholar 86Post C Eriksdotter-Behm K Dependence of lung uptake of lidocaine in vivo on blood pH.Acta Pharmacol Toxicol. 1982; 51: 136-140Crossref PubMed Scopus (14) Google Scholar Because at greater pH more of the drug is in its base form, it seems that lung uptake increases because more is in the non-ionized, more lipophilic base form. Lung uptake is not affected by hypoxia30Hasegawa K Yukioka H Hayashi M Tatekawa S Fujimori M Lung uptake of lidocaine during hyperoxia and hypoxia in the dog.Acta Anaesthesiol Scand. 1996; 40: 489-495Crossref PubMed Scopus (4) Google Scholar or lung insufficiency.51Jorfeldt L Lewis DH Löfström JB Post C Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion or lung insufficiency.Acta Anaesthesiol Scand. 1983; 27: 5-9Crossref PubMed Scopus (28) Google Scholar Lung uptake may be reduced by some drugs undergoing lung uptake, such as propranolol,71Ochs HR Carstens G Greenblatt DJ Reduction in lidocaine clearance during continuous infusion and by coadministration of propanolol.N Engl J Med. 1980; 303: 373-377Crossref PubMed Scopus (133) Google Scholar but other drugs, such as mepivacaine,51Jorfeldt L Lewis DH Löfström JB Post C Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion or lung insufficiency.Acta Anaesthesiol Scand. 1983; 27: 5-9Crossref PubMed Scopus (28) Google Scholar have no effect on lidocaine lung uptake. Lidocaine can displace nortriptyline from the lungs,87Post C Lewis DH Displacement of nortriptyline and uptake of 14C-lidocaine in the lung after administration of 14C-lidocaine to nortriptyline intoxicated pigs.Acta Pharmacol Toxicol. 1979; 45: 218-224Crossref PubMed Scopus (17) Google Scholar and increases the pulmonary uptake of propranolol.78Pang JA Williams TR Blackburn JP Holt DW Geddes DM Lidocaine increases lung uptake of propranolol.Lung. 1986; 164: 173-183Crossref PubMed Scopus (1) Google Scholar Lung uptake probably does not involve metabolism, as lidocaine accumu" @default.
• W2015983312 created "2016-06-24" @default.
• W2015983312 creator A5077533695 @default.
• W2015983312 date "2003-07-01" @default.
• W2015983312 modified "2023-10-14" @default.
• W2015983312 title "Drug handling by the lungs" @default.
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