Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide

Back, DJ; Tjia, John; Mönig, H.; Ohnhaus, E. E.; Park, B. K.

doi:10.1007/bf00614553

Cited by 46 publications

(27 citation statements)

References 43 publications

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“…A relative order of modulatory potency is established ( Table 1). The increase in reduction of NNK is similar to that with other chemicals found for inhibition of oxidation of NNK and thereby reduce the NNK-induced tumorigenicity (Back et al, 1988;Hanrahan & Gordon, 1984;Hecht et al, 1990;Inaba et al, 1988;Ioannides et al, 1989;Wright et al, 1991). In addition, the results showed that the amount of NNAL formation was significantly increased with the concentration of microsomal proteins.…”

Section: Correlation Between Nnal Formation and The Vitamin Concentrasupporting

confidence: 65%

Effects of Vitamins and Common Drugs on Reduction of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Rat Microsomes

Leung

2001

Archives of Physiology and Biochemistry

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4-(Methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) is a tobacco-specific nitrosamino that requires metabolic activation by cytochrome P450 enzymes. The activation of NNK by cytochrome P450 enzymes leads to the formation of different metabolites. Detoxification of NNK usually occurs via carbonyl reduction to its hydroxyl product, 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL). In the present study, the influences of common vitamins and P450 modulators on the reduction of NNK by rat microsomes were studied. The formation of NNAL but not other metabolites was detected by the described HPLC method. Among the vitamins tested, vitamins E, A (retinol), B6 and B5 were found to be marginal effective upon reduction of NNK while vitamins A (cis-acid), A (trans-acid), D2, D3, K1, K3, B1 and A (crocetin) increased the formation of NNAL from 3 to 21%. The effect of vitamin C-palmitate (<10 microM) was most pronounced followed by crocetin upon reduction of NNK. Clonidine, tolbutamide and atropine slightly increased the reduction of NNK while cimetidine showed no effects. The modulation of NNK reduction could reduce the carcinogenic potential of NNK, since the main detoxification pathway of NNK involves carbonyl reduction.

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Section: Correlation Between Nnal Formation and The Vitamin Concentrasupporting

confidence: 65%

Effects of Vitamins and Common Drugs on Reduction of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Rat Microsomes

Leung

2001

Archives of Physiology and Biochemistry

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“…(175)) is a weak inhibitor of CYP2C9 in vitro [990], with an apparent K i of 327 M. Coadministration of cimetidine 1 g/day had no effect on the kinetics of tolbutamide but a higher dose (1.6 g/day) decreased the systemic and metabolic clearances of tolbutamide by about 40% in healthy volunteers [1358]. Cimetidine caused only a modest reduction in the clearance of phenytoin, although clinically significant increases in plasma phenytoin levels have been observed in patients receiving long-term phenytoin treatment [1359].…”

Section: Cimetidinementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

149

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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“…No effect No ADRAC (1982); Chellingsworth et al (1988); Ellis et at (1984); Kirch et al (1981); Mutschler et at (1984) able and possibly dependent on the dosage of cimetidine studied. When cimetidine was administered at dosages of 1200 and 1600 mgjday, tolbutamide half-life and AUC increased and clearance decreased (Back et al 1988;Cate et al 1986). However, at lower doses of 800 and 1000 mgjday, cimetidine had no significant effect on tolbutamide pharmacokinetics (Back et al 1988;Dey et al 1983;Stockley et al 1986).…”

Section: Other Agentsmentioning

confidence: 90%

“…When cimetidine was administered at dosages of 1200 and 1600 mgjday, tolbutamide half-life and AUC increased and clearance decreased (Back et al 1988;Cate et al 1986). However, at lower doses of 800 and 1000 mgjday, cimetidine had no significant effect on tolbutamide pharmacokinetics (Back et al 1988;Dey et al 1983;Stockley et al 1986). In contrast, Adebayo & Coker (1988) reported that cimetidine 1200 mgjday had no effect on tolbutamide disposition.…”

Section: Other Agentsmentioning

confidence: 90%

“…Monitor drug Choonara et al (1986); Hetzel et al levels, adjust (1979) Toon et al (1986Toon et al ( , 1987; Wallin et al (1979) No Pachon et al (1989); Puff et al (1989); Zylber-Katz (1988) No Fraley et al (1983); Garty et al (1986); Jordaens et al (1981); Ochs et al (1984) No Harvey et al (1984) No Gugler et al (1983) No Back et al (1988); Cate et al (1986); Dey et al (1983); Stockley et al (1986) Abbreviations: C = serum/blood/plasma drug concentration; AUC = area under the concentration-time curve; t'l2 = elimination halflife; CL = clearance.…”

Section: Theophyllinementioning

confidence: 97%

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Clinical Relevance of Cimetidine Drug Interactions

Shinn

1992

Drug Safety

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The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

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Selective inhibition of drug oxidation after simultaneous administration of two probe drugs, antipyrine and tolbutamide

Cited by 46 publications

References 43 publications

Effects of Vitamins and Common Drugs on Reduction of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Rat Microsomes

Effects of Vitamins and Common Drugs on Reduction of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone in Rat Microsomes

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Clinical Relevance of Cimetidine Drug Interactions

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