First pass uptake of 14C-propranolol by the lung.

Geddes, Duncan M.; Nesbitt, Kenneth A.; Traill, Thomas A.; Blackburn, J. P.

doi:10.1136/thx.34.6.810

Cited by 43 publications

(18 citation statements)

References 4 publications

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“…The lungs occupy a strategic position in the systemic blood circulation and, like the liver, pulmonary tissues have the capacity for metabolism and uptake of drugs. The ability of the lungs to accumulate and metabolize drugs has received increased interest in recent years and several drugs including lignocaine (Jorfeldt et al, 1979), propranolol (Geddes et al, 1979) and morphine (Persson et al, 1986) have been found to show considerable pulmonary uptake. In contrast, significant pulmonary clearance has been demonstrated for only a few drugs (Roth, 1984;Roth & Wiersma, 1979).…”

Section: Introductionmentioning

confidence: 99%

Pulmonary disposition of pethidine in postoperative patients.

Persson

Hartvig

Wiklund

et al. 1988

Brit J Clinical Pharma

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1 Two methods of pethidine administration, namely constant-rate infusion and single i.v. injection, were used to assess the pulmonary disposition of the drug in 10 postoperative patients. Using two sites of blood sampling, the pulmonary extraction ratio was determined. 2 Pronounced pulmonary uptake of pethidine was found in all patients (n = 10). On the other hand, there was no significant evidence of pulmonary clearance. 3 The mean total plasma clearance was 810 ml min-' and the volume of distribution was 3.1 1 kg-1. 4 A flow model was used to describe the disposition of pethidine in man. The concentration-time profiles calculated by the model were in accordance with observed data. The data showed that both pulmonary uptake and pulmonary release of pethidine were rapid. 5 Constant-rate infusion was found advantageous in the determination of pulmonary extraction, with respect to the accuracy and precision of the results. The extraction obtained after a single injection may be overestimated on account of uptake of the drug by the lungs.

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Section: Introductionmentioning

confidence: 99%

Pulmonary disposition of pethidine in postoperative patients.

Persson

Hartvig

Wiklund

et al. 1988

Brit J Clinical Pharma

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“…In rats, the pharmacokinetic parameters after intravenous and intra-arterial administration showed that the lung contributed to the in vivo elimination of drugs such as propofol (Raoof et al, 1996), phenol (Cassidy and Houston, 1980), and 1-naphthol (Mistry and Houston, 1985). In humans, a high percentage of propranolol (75%) (Geddes et al, 1979) and lidocaine (60%) (Jorfeldt et al, 1979) is taken up by the lung during the first passage of a drug through the pulmonary circulation. These reports support the importance of the lung for the elimination of drugs.…”

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confidence: 99%

Contribution of Rat Pulmonary Metabolism to the Elimination of Lidocaine, Midazolam, and Nifedipine

Aoki¹,

Okudaira²,

Haga³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The contribution of the lung to drug metabolism was investigated in rats and the possibility of prediction of in vivo metabolism from in vitro studies using rat pulmonary microsomes was assessed. Lidocaine, midazolam, or nifedipine was administered to rats at a dose of 10 mg/kg by the intra-arterial, intravenous, and intraportal routes. The pulmonary extraction ratios of lidocaine, midazolam, and nifedipine, calculated from the area under the time-plasma concentration curve (AUC) after the intra-arterial and intravenous administrations, were 39.0 ؎ 0.5, 18.3 ؎ 0.7, and 12.3 ؎ 0.3%, respectively. The hepatic extraction ratios of lidocaine, midazolam, and nifedipine, calculated from the AUC after the intraportal and intravenous administrations, were 68.0 ؎ 3.3, 52.6 ؎ 0.4, and 13.5 ؎ 0.2%, respectively. These results showed that both the liver and the lung contributed to the metabolism of these drugs. The above in vivo pulmonary extraction ratios correlated with the in vitro intrinsic clearance values, which were corrected with the protein unbound ratio in microsomes and plasma, suggesting that pulmonary extraction ratios can be predicted quantitatively from in vitro data. The pulmonary intrinsic clearance values of lidocaine, midazolam, and nifedipine in rat microsomes were lower than their hepatic intrinsic clearance, showing that there was an organ difference in metabolism between the liver and lung. Our results support the importance of the estimation of pulmonary metabolism to predict the total clearance more accurately.The lung has a variety of drug-metabolizing enzymes, such as the CYP1A, 2A, 2B, 2E, 2F, 2J, 3A, and 4B families (Dees et al., 1982;Domin et al., 1986;de Waziers et al., 1990;Nhamburo et al., 1990;Ueno and Gonzalez, 1990;Debri et al., 1995;Zeldin et al., 1996). The lung is an efficient organ for extracting drugs from the blood circulation because all cardiac output goes through it (Perreault et al., 1993). In addition, drugs can undergo first-pass metabolism in the lung after not only oral administration but also intravenous administration. These characteristics of the lung suggest that the lung plays an important role in the elimination of a variety of compounds.Lidocaine (Tanaka et al., 1994), testosterone (Imaoka et al., 1989), aminopyrine (Funae et al., 1985), and p-nitroanisole (Funae et al., 1985) are metabolized in pulmonary microsomes of rats. In rats, the pharmacokinetic parameters after intravenous and intra-arterial administration showed that the lung contributed to the in vivo elimination of drugs such as propofol (Raoof et al., 1996), phenol (Cassidy and Houston, 1980), and 1-naphthol (Mistry and Houston, 1985). In humans, a high percentage of propranolol (75%) (Geddes et al., 1979) and lidocaine (60%) (Jorfeldt et al., 1979) is taken up by the lung during the first passage of a drug through the pulmonary circulation. These reports support the importance of the lung for the elimination of drugs.The lung has CYP3A families (Krishna and Klotz, 1994;Debri et al., 1995;Anttila...

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“…Appreciable metabolism of the drug during its first pass through the lungs is unlikely; there was negligible metabolism by the isolated perfused rat lung in the experiments of Dollery and Junord [22] or Geddes et al [18]. Taking into account the fact that the IMP lung image was similar to the 99mTc-macroaggregated albumin lung perfusion image during the first pass, it is suggested that the decrease in pulmonary blood flow plays the most important role in the poor accumulation of IMP in cancerous tissues.…”

Section: Discussionmentioning

confidence: 96%

“…Radioactive amines have been used to explore lung metabolic functions [17,18]. In 1981, ~23I-IMP was introduced by Rahimian and co-workers as a tracer of lung metabolic functions because studies using this agent in brain imaging indicated that it was avidly taken up by the lungs [19].…”

Section: Discussionmentioning

confidence: 99%

N-Isopropyl-p-iodoamphetamine receptors in normal and cancerous tissue of the human lung

et al. 1993

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N-Isopropyl-p-iodoamphetamine (IMP) receptors in normal human lung tissue were characterized using a radioligand binding assay with iodine-125 IMP as the ligand. Saturation binding studies revealed the presence of two binding sites with dissociation constant (Kd) values of 53 +/- 2 and 4687 +/- 124 nM and maximum binding capacity (Bmax) values of 7 +/- 1 and 133 +/- 27 pmol/mg protein (n = 5) respectively. The IC50 values of various amines were as follows: IMP, 9 x 10(-5) M; propranolol, 5 x 10(-4) M; haloperidol, 6 x 10(-4) M; ketamine, 9 x 10(-3) M; dopamine, 1 x 10(-2) M. The IMP receptors of cancerous tissue obtained from human lung also had two binding sites with Kd values of 54 +/- 2 and 5277 +/- 652 nM and Bmax values of 7 +/- 1 and 103 +/- 21 pmol/mg protein (n = 3) respectively. There was no significant difference in binding parameters between normal and cancerous lung tissue. These results demonstrate the existence of IMP receptors and suggest that cancer does not affect the nature of IMP receptors in human lung tissue.

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First pass uptake of 14C-propranolol by the lung.

Cited by 43 publications

References 4 publications

Pulmonary disposition of pethidine in postoperative patients.

Pulmonary disposition of pethidine in postoperative patients.

Contribution of Rat Pulmonary Metabolism to the Elimination of Lidocaine, Midazolam, and Nifedipine

N-Isopropyl-p-iodoamphetamine receptors in normal and cancerous tissue of the human lung

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