In Vitro, Pharmacokinetic, and Pharmacodynamic Interactions of Ketoconazole and Midazolam in the Rat

Kotegawa, Tsutomu; Laurijssens, Bart; Moltke, Lisa L. von; Cotreau, Monette M.; Perloff, Michael D.; Venkatakrishnan, Karthik; Warrington, Jill; Granda, Brian; Harmatz, Jerold S.; Greenblatt, David J.

doi:10.1124/jpet.102.035972

Cited by 96 publications

(94 citation statements)

References 34 publications

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“…The present results support the importance of pulmonary metabolism for drugs that are CYP3A substrates and have low migration into the systemic circulation. As observed in our studies, the total clearances of lidocaine and midazolam were higher than the hepatic blood flow in rats (Shand et al, 1975;Kotegawa et al, 2002), suggesting that extrahepatic organs contribute to the elimination of these compounds. In addition, the slope of the correlation line between CL tot, observed determined from AUC and CL tot, calculated determined from the extraction ratio was approximately 1 (Fig.…”

Section: Discussionsupporting

confidence: 65%

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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Section: Discussionsupporting

confidence: 65%

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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“…The CYP3A4-dependent interaction by food-derived agents may be related to the high level expression of CYP3A4 in the small intestine, as well as its broad substrate specificity (Fujita 2004). It has been confirmed that role of intestinal metabolism is significantly greater than hepatic in the firstpass effect for some drugs, e.g., cyclosporine A and midazolam (Isin and Guengerich 2007;Kanazu et al 2005;Kotegawa et al 2002;Paine et al 1996). Even more than half a percent of orally administered cyclosporine A is metabolized by enterocytes (Hebert 1997).…”

Section: Introductionmentioning

confidence: 93%

Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Pałasz

Wiaderkiewicz

et al. 2011

Genes Nutr

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It has been established beyond doubt that, as well as the liver, the small intestine is an important site of first-pass metabolism of numerous drugs, food components and toxic xenobiotics. However, there is not much information available about age-dependent changes of intestinal biotransformation pathways. In the present paper, we evaluated the relationships between intestinal cytochrome P450 complex activity and the age of animals. The study was carried out on male Sprague-Dawley rats (n = 5) from 5 age series: 0.5-, 2-, 4-, 20-, and 28 months old. Animals at every age series were divided into 4 groups: control and three groups of rats treated with the CYP450 specific inducers: phenobarbital, b-naphtoflavone and dexamethasone, respectively. RNA was isolated from intestinal mucosa, and then standard RT-PCR was used for the analysis of CYP1A1, CYP2B1/2 and CYP3A1 mRNA expression. Additionally, the activities of NADPH-cytochrome P450 and NADH-cytochrome b 5 reductases in the microsomal fraction were biochemically estimated. The constitutive intestinal CYP1A1 mRNA expression changes during maturation and aging. Inducibility of CYP1A1 gene was evident in intestinal mucosa at 2-, 4-and 20-month-old rats. A similar pattern of changes was observed for CYP2B1/2 isoforms. CYP3A1 mRNA expression was not detected in small intestine of 2-week-old rats. In matured rats, constitutive intestinal CYP3A1 expression was low, although after induction, significant increases in CYP3A1 mRNA amount were noted in aged individuals. Intestinal activity of both analyzed reductases was lowest in immature rats and highest in 28-month-old animals. In conclusion, the activity of cytochrome P450 complex in rat small intestine was not decreased by the aging processes, so the high rate of oxidative metabolic reactions in intestinal mucosa can be maintained till the advanced life stage.

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“…First, there was no drug effect upon locomotion activity at test. Second, the elimination half-life of MDZ has been observed to be 30 minutes (Kotegawa et al, 2002). Given this fact, at 120 minutes post-administration of a 0.09 or 0.18 mg/kg MDZ dose, only a trace amount of the drug should be present in the system.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of ethanol and midazolam upon the devaluation of an aversive memory in infant rats

Pautassi

Nizhnikov

Molina

et al. 2007

Alcohol

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In infant rats, low doses of ethanol have been found to attenuate the aversive representation of an unconditioned stimulus (US) as assessed through a revaluation paradigm. This may be explained by early anxiolytic properties of EtOH. The present set of experiments was aimed at analyzing possible mechanisms of these putative anti-anxiety effects of EtOH. In a the first experiment, EtOH's effects upon the expression of citric acid-induced distress calls were compared with varying doses of midazolam (MDZ), a fast-acting GABA A agonist. Similar calming effects of 0.5 g/kg EtOH and 0.09 mg/kg MDZ were observed. Both drugs were then assessed in their capability to alter the expression of a conditioned aversion by devaluing the US. Aversive conditioning was conducted on postnatal day 14 (PD14) by pairing a lemon odor (conditioned stimulus, CS) with intraoral stimulation of citric acid (US). Control animals experienced both stimuli in an explicitly unrelated fashion. On PD 15 pups were briefly exposed to the citric acid solution under the effects of 0.5 g/kg EtOH, 0.09 mg/kg MDZ, or the respective vehicle for each drug. Pups were then tested in a two-way odor preference test (lemon vs. cineole). Both vehicle and MDZ-treated animals spent significantly less time near the lemon CS, thus expressing a citric-acid mediated odor aversion. This conditioned response was completely inhibited in pups that received 0.5 g/kg EtOH. Locomotor patterns at test were not affected by either EtOH or MDZ administration. A higher dose of MDZ (0.18 mg/kg, i.p) was also ineffective in attenuating the aversive memory. In summary, EtOH's devaluating capabilities are not shared by MDZ, indicating that these effects of EtOH may not be GABA-mediated. Appetitive motivational properties of EtOH or non-GABA A -mediated anti-anxiety effects (i.e, NMDA-related) could underlie this devaluation effect of ethanol.

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In Vitro, Pharmacokinetic, and Pharmacodynamic Interactions of Ketoconazole and Midazolam in the Rat

Cited by 96 publications

References 34 publications

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

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

Age-related changes in the mRNA levels of CYP1A1, CYP2B1/2 and CYP3A1 isoforms in rat small intestine

Differential effects of ethanol and midazolam upon the devaluation of an aversive memory in infant rats

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