Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174*

Goldberg, Michael R.; Lo, Man Wai; Deutsch, Paul; Wilson, Susan E.; McWilliams, Edward J.; McCrea, Jacqueline B.

doi:10.1016/s0009-9236(96)80004-x

Cited by 35 publications

(11 citation statements)

References 11 publications

(2 reference statements)

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“…Coadministration of losartan and cimetidine led to an increase of~18% in AUC of losartan but did not affect the pharmacokinetics of EXP3174 . Coadministration of losartan and phenobarbital led to a reduction of~20% in the AUC of losartan and EXP3174 (Goldberg et al, 1996). A somewhat greater interaction (~40% reduction in the AUC of EXP3174 and~30% reduction in the AUC of losartan) has been reported with rifampin (Williamson et al, 1998).…”

Section: G Pharmacokinetic Drug-drug Interactionsmentioning

confidence: 94%

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

et al. 2013

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Section: G Pharmacokinetic Drug-drug Interactionsmentioning

confidence: 94%

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

et al. 2013

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“…The plasma concentration of the principal metabolite of phenytoin, 4'-HPPH, was significantly increased after barbiturate therapy. Administration of phenobarbitone at 100 mg/day for 16 days to healthy subjects decreased the AUC of losartan and its metabolite E-3174 by about 20% [1532], probably due to modest induction of CYP2C9 and 3A4. Half-life values of losartan and E-3174 were not affected.…”

Section: Drug-drug Interactions Owing To Induction Of Cyp2c9mentioning

confidence: 96%

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

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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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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“…Similar to phenytoin, phenobarbitone treatment appears to have only a modest effect on losartan clearance. Sub‐acute administration of phenobarbitone reduced mean losartan AUC by about 20% [73], but whether this reflects induction of CYP2C9 or CYP3A4, both of which contribute to losartan biotransformation, is unclear.…”

Section: Factors Affecting Cyp2c9 Activitymentioning

confidence: 99%

Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

Miners

Birkett

1998

Brit J Clinical Pharma

729

533

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Accumulating evidence indicates that CYP2C9 ranks amongst the most important drug metabolizing enzymes in humans. Substrates for CYP2C9 include fluoxetine, losartan, phenytoin, tolbutamide, torsemide, S-warfarin, and numerous NSAIDs. CYP2C9 activity in vivo is inducible by rifampicin. Evidence suggests that CYP2C9 substrates may also be induced variably by carbamazepine, ethanol and phenobarbitone. Apart from the mutual competitive inhibition which may occur between alternate substrates, numerous other drugs have been shown to inhibit CYP2C9 activity in vivo and/or in vitro. Clinically significant inhibition may occur with coadministration of amiodarone, fluconazole, phenylbutazone, sulphinpyrazone, sulphaphenazole and certain other sulphonamides. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino acid residues 144 (Arg144Cys) and 359 (Ile359Leu) of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, although the frequency of this allele is relatively low. Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. Individualisation of dose is essential for those CYP2C9 substrates with a narrow therapeutic index.

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Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174*

Cited by 35 publications

References 11 publications

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

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

Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

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