Extrahepatic First-Pass Metabolism of Nifedipine in the Rat

Grundy, John S.; Eliot, Lise; Foster, Robert T.

doi:10.1002/(sici)1099-081x(199708)18:6<509::aid-bdd38>3.0.co;2-5

Cited by 44 publications

(40 citation statements)

References 11 publications

(15 reference statements)

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“…The compounds were therefore metabolized in both liver and lung, leading to lower amounts of drugs being able to reach the systemic circulation after intravenous or oral administration. The reported values for the bioavailability of lidocaine, midazolam, and nifedipine in rats are 16, 12, and 61%, respectively (de Leede et al, 1983;Grundy et al, 1997;Higashikawa et al, 1999). The present results support the importance of pulmonary metabolism for drugs that are CYP3A substrates and have low migration into the systemic circulation.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Student's t test was used for statistical analysis of differences between B6 and CL strains. dmd.aspetjournals.org presystemic extraction in small intestine in pharmacokinetic studies in rats (Grundy et al, 1997), 2) increased bioavailability of oral nifedipine in rats suffering from decreased intestinal P450 and P450 reductase contents as a result of repeated exposure to the anticancer drug 5-fluorouracil (Yoshisue et al, 2001), 3) increased bioavailability of oral nifedipine in humans (Bailey et al, 1991(Bailey et al, , 1998 and rats (Grundy et al, 1997(Grundy et al, , 1998Mohri et al, 2000) given concentrated grapefruit juice (or active components), which inhibits intestinal, but apparently not hepatic, CYP3A-mediated drug metabolism, and 4) a reduction in oral, but not intravenous, nifedipine bioavailability in patients during coadministration with rifampin, a CYP3A inducer (Holtbecker et al, 1996). Nonetheless, the effects of the interacting drugs in these studies were not strictly specific to P450 enzymes or to the intestine.…”

Section: Pharmacokinetic Parameters For Nifedipine Clearancementioning

confidence: 99%

“…A role for extrahepatic tissue P450 enzymes in the in vivo disposition of cyclophosphamide was subsequently demonstrated through comparison of the pharmacokinetics of cyclophosphamide metabolism between the LCN and CL-LCN mice (Gu et al, 2007). It should be noted that none of these studies compared the impact of CPR deficiency on the disposition of intraperitoneally administered drugs with the impact on orally administered drugs; for oral drugs, the small intestine is expected to play a greater role in first-pass metabolism than for drugs given intraperitoneally (Grundy et al, 1997).…”

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confidence: 99%

Role of Small Intestinal Cytochromes P450 in the Bioavailability of Oral Nifedipine

Zhang¹,

Kaminsky²,

Dunbar³

et al. 2007

Drug Metab Dispos

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ABSTRACT:To determine the effect of intestinal cytochrome P450 (P450) enzymes on the bioavailability of oral drugs, we have examined the metabolism of nifedipine, an antihypertensive drug and a model substrate of CYP3A4, in mouse models having deficient expression of the NADPH-cytochrome P450 reductase. Initial studies were performed on Cpr-low (CL) mice, which have substantial decreases in Cpr expression in all tissues examined, including the small intestine. In CL mice, area under the concentration-time curve (AUC) values for blood nifedipine after intraperitoneal and oral dosing were 1.8-and 4.0-fold, respectively, higher than in wild-type mice, despite increased expression of multiple P450 enzymes in both liver and intestine. The greater extent of the increase in the AUC value for oral than for intraperitoneal nifedipine suggested that intestinal P450s influence the bioavailability of oral nifedipine, a notion supported by results from further studies on LCN and CL-LCN mice. The LCN mice, which have liver-specific Cpr deletion, had 6.9-fold higher AUC values and 2.2-fold higher C max values for blood nifedipine than did wild-type mice after oral nifedipine, consistent with the critical role of hepatic P450s in systemic nifedipine clearance. However, in the CL-LCN mice, which have global decreases in Cpr expression in all tissues examined and Cpr deletion in the liver, AUC and C max values for oral nifedipine were, respectively, 2.2-and 1.8-fold higher than in LCN mice, confirming the fact that P450-catalyzed metabolism in the small intestine, the portal-of-entry organ for oral drugs, plays an important role in the first-pass clearance of oral nifedipine.

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“…Although the bioavailability of orally administered nifedipine is reported to range from about 45 to 58% in the rat, which compares favorably to human beings, the contribution of metabolic enzymes in small intestine and liver to the firstpass effect was expected to be different between rats and human beings. 27) In this study, we used grapefruit juice, a well-characterized natural CYP3A inhibitor studied in patients, as a positive control, that would be helpful to approximate the data of animal experiment to the case of human beings.…”

Section: Discussionmentioning

confidence: 99%

Does a Kampo Medicine Containing Schisandra Fruit Affect Pharmacokinetics of Nifedipine Like Grapefruit Juice?

Makino

Mizuno

Mizukami

2006

Biological & Pharmaceutical Bulletin

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Herb-drug interaction has attracted attention as medicinal topics recently. However, the drug information is sometimes confusing. Previous in vitro studies revealed that schisandra fruit had strong inhibitory effect on CYP3A4 and claimed the possibilities of its herb-drug interaction. In the present study, we evaluated the inhibitory effects of schisandra fruit and shoseiryuto, an herbal formula in Japanese traditional kampo medicine containing eight herbal medicines including schisandra fruit, on rat CYP3A activity in vitro, and the effect of shoseiryuto on pharmacokinetics of nifedipine in rats, in comparison with those of grapefruit juice, a well-characterized natural CYP3A inhibitor. Shoseiryuto and its herbal constituents, schisandra fruit, ephedra herb and cinnamon bark exhibited in vitro inhibitory effect of CYP3A. Although shoseiryuto inhibited rat CYP3A activity in vitro with a degree comparable to grapefruit juice, shoseiryuto did not significantly affect a plasma concentration profile of nifedipine in rats as grapefruit juice did. These results indicate that in vivo experiments using the extract of herbal medicine prepared with the same dosage form as patients take are necessary to provide proper information about herb-drug interaction.

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Extrahepatic First-Pass Metabolism of Nifedipine in the Rat

Cited by 44 publications

References 11 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

Role of Small Intestinal Cytochromes P450 in the Bioavailability of Oral Nifedipine

Does a Kampo Medicine Containing Schisandra Fruit Affect Pharmacokinetics of Nifedipine Like Grapefruit Juice?

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