Biotransformation of Nisoldipine in Man

Scherling, D.; Ahr, G.; Karl, Wolfgang

doi:10.1007/978-3-642-73010-8_10

Cited by 19 publications

(19 citation statements)

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“…The absence of double peaks in the (tap) water or both regular-strength juice group plasma profiles would tend to rule out the possibility of enterohepatic circulation. As well, nifedipine is rapidly, extensively, and presumably irreversibly metabolized via oxidation in the rat, with the principal metabolite further metabolized to several other biotransformation products which themselves can undergo enterohepatic circulation [34,35]. Given that the pK a -value of nifedipine is − 0.9 [55], the drug exists primarily in its unprotonated form at all pH conditions in the GI tract and thus pH-dependent solubility and absorption can be ruled out.…”

Section: Resultsmentioning

confidence: 99%

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Grapefruit juice and orange juice effects on the bioavailability of nifedipine in the rat

Grundy¹,

Eliot²,

Kulmatycki³

et al. 1998

Biopharm. Drug Dispos.

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Section: Resultsmentioning

confidence: 99%

“…Nifedipine is well absorbed ( ] 90%) from the gut lumen of human beings and rats [34][35][36][37][38][39][40]. After absorption, nifedipine is metabolized by oxidative mechanisms -involving CYP 3A isozymes-to a pharmacologically inactive nitropyridine analog, which is subsequently metabolized to more polar compounds [41 -43].…”

Section: Introductionmentioning

confidence: 99%

Grapefruit juice and orange juice effects on the bioavailability of nifedipine in the rat

Grundy¹,

Eliot²,

Kulmatycki³

et al. 1998

Biopharm. Drug Dispos.

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“…Nimodipine is metabolized by CYP3A4 in both the liver and small intestine Scherling et al, 1991) and the absorption of nimodipine in the intestinal mucosa is inhibited by P-glycoprotein efflux pump (Saeki et al, 1993). In the small bowel, P-glycoprotein is co-localized at the apical membrane of the cells with CYP3A4 (Watkins, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Usually only the parent compound is active and most of the metabolic steps involve reactions catalyzed by cytochrome P450 (CYP) enzymes. CYP enzymes have been shown to catalyze pyridine formation, methyl hydroxylation, and various modes of sidechain oxidation Scherling et al, 1991).…”

mentioning

confidence: 99%

Effects of Kaempferol, an Antioxidant, on the Bioavailability and Pharmacokinetics of Nimodipine in Rats

Park¹,

Choi²

2011

Journal of Pharmaceutical Investigation

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− The aim of this study was to investigate the effects of kaempferol on the pharmacokinetics of nimodipine in rats. Nimodipine and kaempferol interact with cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in kaempferol being taken concomitantly with nimodipine as a combination therapy to treat orprevent cardiovascular disease. The effect of kaempferol on P-gp and CYP3A4 activity was evaluated and Pharmacokinetic parameters of nimodipine were determined in rats after an oral (12 mg/kg) and intravenous (3 mg/kg) administration of nimodipine to rats in the presence and absence of kaempferol (0.5, 2.5, and 10 mg/kg). Kaempferol inhibited CYP3A4 enzyme activity in a concentration-dependent manner with 50% inhibition concentration (IC 50 ) of 17.1 µM. In addition, kaempferol significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ ADR cells overexpressing P-gp. Compared to the oral control group, the area under the plasma concentration-time curve (AUC 0-∞ ) and the peak plasma concentration (C max ) of nimodipine significantly increased, respectively. Consequently, the absolute bioavailability of nimodipine in the presence of kaempferol (2.5 and 10 mg/kg) was 29.1-33.3%, which was significantly enhanced compared to the oral control group (22.3%). Moreover, the relative bioavailability of nimodipine was 1.30-to 1.49-fold greater than that of the control group. The pharmacokinetics of intravenous nimodipine was not affected by kaempferol in contrast to those of oral nimodipine. Kaempferol significantly enhanced the oral bioavailability of nimodipine, which might be mainly due to inhibition of the CYP3A4-mediated metabolism of nimodipine in the small intestine and /or in the liver and to inhibition of the P-gp efflux transporter in the small intestine by kaempferol. The increase in oral bioavailability of nimodipine in the presence of kaempferol should be taken into consideration of potential drug interactions between nimodipine and kaempferol.

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“…Several examples can be found in published literature of inferred or demonstrated hydroxylation of the carbon ␣-to an ester linkage, a number of which lead to ester cleavage (Guengerich et al, 1988;Funaki et al, 1989;Scherling et al, 1992;Dunkov et al, 1997), due to the collapse of the resulting hemiacetal functionality. In cases where the ester is cyclic, i.e., in the form of a lactone (Chauret et al, 1995;Holmes et al, 1995;Delorme et al, 1996;Jacobs and Metzler, 1999), the product of ␣-carbon hydroxylation is stable and can be observed directly.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Rofecoxib in Vitro Using Human Liver Subcellular Fractions

Slaughter¹,

Takenaga²,

Lü³

et al. 2003

Drug Metabolism and Disposition

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The metabolism of rofecoxib, a potent and selective inhibitor of cyclooxygenase-2, was examined in vitro using human liver subcellular fractions. The biotransformation of rofecoxib was highly dependent on the subcellular fraction and the redox system used. In liver microsomal incubations, NADPH-dependent oxidation of rofecoxib to 5-hydroxyrofecoxib predominated, whereas NADPHdependent reduction of rofecoxib to the 3,4-dihydrohydroxy acid metabolites predominated in cytosolic incubations. In incubations with S9 fractions, metabolites resulting from both oxidative and reductive pathways were observed. In contrast to microsomes, the oxidation of rofecoxib to 5-hydroxyrofecoxib by S9 fractions followed two pathways, one NADPH-dependent and one NAD ؉ -dependent (non-cytochrome P450), with the latter accounting for about 40% of total activity. The 5-hydroxyrofecoxib thus formed was found to undergo NADPH-dependent reduction ("back reduction") to rofecoxib in incubations with liver cytosolic fractions. In incubations with dialyzed liver cytosol, net hydration of rofecoxib to form 3,4-dihydro-5-hydroxyrofecoxib was observed, whereas the 3,4-dihydrohydroxy acid derivatives were formed when NADPH was present. Although 3,4-dihydro-5-hydroxyrofecoxib could be reduced to the 3,4-dihydrohydroxy acid by cytosol in the presence of NADPH, the former species does not appear to serve as an intermediate in the overall reductive pathway of rofecoxib metabolism. In incubations of greater than 2 h with S9 fractions, net reductive metabolism predominated over oxidative metabolism. These in vitro results are consistent with previous findings on the metabolism of rofecoxib in vivo in human and provide a valuable insight into mechanistic aspects of the complex metabolism of this drug.Rofecoxib (VIOXX, a registered trademark of Merck and Co., Inc.) is a potent and selective inhibitor of cyclooxygenase-2 (COX-2 1 ), which is indicated for the treatment of osteoarthritis, rheumatoid arthritis, and pain. It has been shown to cause significantly fewer gastrointestinal side effects than naproxen, a nonselective COX inhibitor (Bombardier et al., 2000), consistent with the hypothesis that COX-2 selective inhibitors exhibit a gastrointestinal safety advantage over nonselective COX inhibitors (Donnelly and Hawkey, 1997;Jouzeau et al., 1997).In previous reports from this laboratory, the absorption, distribution, metabolism, and excretion of rofecoxib were examined in the rat, dog, and human (Halpin et al., 2000(Halpin et al., , 2002. Metabolism studies in laboratory animals and humans indicated that rofecoxib undergoes complex metabolism involving both oxidative and reductive reactions. Although the metabolic pathways of rofecoxib were qualitatively similar between the rat and human, oxidation to 5-hydroxyrofecoxib (5-hydroxyR) predominated in rats (Halpin et al., 2000), whereas reduction of rofecoxib to the corresponding isomeric 3,4-dihydrohydroxy acid (DHHA) derivatives was...

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Biotransformation of Nisoldipine in Man

Cited by 19 publications

References 0 publications

Grapefruit juice and orange juice effects on the bioavailability of nifedipine in the rat

Grapefruit juice and orange juice effects on the bioavailability of nifedipine in the rat

Effects of Kaempferol, an Antioxidant, on the Bioavailability and Pharmacokinetics of Nimodipine in Rats

Metabolism of Rofecoxib in Vitro Using Human Liver Subcellular Fractions

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