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

Abstract

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...

Contribution of Baicalin on the Plasma Protein Binding Displacement and CYP3A Activity Inhibition to the Pharmacokinetic Changes of Nifedipine in Rats In Vivo and In Vitro

“…To explore whether baicalin can inhibit the metabolism of nifedipine, an in vitro incubation study in RLMs was performed in a subsequent study. These findings showed that the K m and V max values were consistent with previous observations [49], and baicalin was a relatively weak inhibitor of CYP3A in RLMs, with a competitive inhibitory effect. However, the pharmacokinetics of baicalin studies showed that the C max values of baicalin in rats treated with baicalin at 0.225 g/kg and 0.45 g/kg were 754.8 mg/L and 1280.4 mg/L, respectively.…”

Effect of CYP1A2 polymorphism on the pharmacokinetics of agomelatine in Chinese healthy male volunteers

“…The liver is the major clearance organ for many drugs, and human liver microsomes enable the prediction of the metabolic clearance of drugs in the liver of humans, but there are also many drugs that have been considered as outliers in the prediction of elimination using human liver microsomes, such as propranolol, lidocaine, midazolam and nifedipine, and these drugs are eliminated almost exclusively by the liver, with a high hepatic extraction ratio. Under these conditions, body clearance is equal to hepatic clearance and corresponds to hepatic blood flow .…”

Time-Dependent Interaction of Ritonavir in Chronic Use: The Power Balance Between Inhibition and Induction of P-Glycoprotein and Cytochrome P450 3A

“…Most available drugs are metabolized and mediated by several enzymes and transporters and the induction effect of RTV on them could not be uniform. 24 The activities of enzymes and transporters in other organs such as lung and kidney could also not be ruled out, 25 and HIV-infected patients often received the RTV-boosted HAART regimen twice a day, whereas once-daily regimen has recently become available. 26,27 Moreover, not only the dose interval of RTV-boosted HAART regimen but also the elimination half-lives of concomitant drugs and RTV itself in humans could further complicate the present time-dependent interaction.…”