Effect of cimetidine and phenobarbital on metabolite kinetics of omeprazole in rats

Park, Eunja; Cho, Hea-Young; Lee, Yong-Bok

doi:10.1007/bf02972986

Cited by 12 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Omeprazole is known to be primarily metabolized by CYP2C19 and CYP3A4 in humans (Andersson et al, 1994;Chang et al, 1995;Andersson, 1996). Its metabolism can be altered by coadministration with phenobarbital (Park et al, 2005). Although the primary P450 enzymes metabolizing omeprazole in mice are not defined yet, we select CYP2C29 and CYP3A11 as representative members of CYP2C and CYP3A subfamilies, respectively, in this study.…”

Section: Introductionmentioning

confidence: 99%

Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice

et al. 2017

View full text Add to dashboard Cite

Drug-drug interactions (DDIs) occur when the action of one drug interferes with or alters the activity of another drug taken concomitantly. This can lead to decreased drug efficacy or increased toxicity. Because of DDIs, physicians in the clinical practice attempt to avoid potential interactions when multiple drugs are coadministrated; however, there is still a large knowledge gap in understanding how drugs taken in the past can contribute to DDIs in the future. The goal of this study was to investigate the consequence of neonatal drug exposure on efficacy of other drugs administered up through adult life. We selected a mouse model to test phenobarbital exposure at a neonatal age and its impact on efficacy of omeprazole in adult life. The results of our experiment show an observed decrease in omeprazole's ability to raise gastric pH in adult mice that received single or multiple doses of phenobarbital at a neonatal age. This effect may be associated with the permanent induction of cytochrome P450 enzymes in adult liver after neonatal phenobarbital treatment. Our data indicates that DDIs may result from drugs administered in the past in an animal model and should prompt re-evaluation of how DDIs are viewed and how to avoid long-term DDIs in clinical practice.

show abstract

Section: Introductionmentioning

confidence: 99%

Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Phenobarbital (PB), one of the antiepileptic drugs, induces drug-metabolizing enzymes in laboratory animals and human, including CYP 2B and 3A (Park et al, 2005). PB has been widely used as a prototype inducer for drug metabolism in pharmacological and toxicological investigations.…”

Section: Introductionmentioning

confidence: 99%

“…Particularly, the in vivo interaction of rutaecarpine with CYP inducers and inhibitors has not been investigated to date. To develop rutaecarpine as an anti-inflammatory drug, our group has focused our research on its metabolism (Lee et al, 2004a, Park et al, 2005 and, for this reason, it was necessarily required to study the possible interaction of rutaecarpine with a well known CYP inducer, PB.…”

Section: Introductionmentioning

confidence: 99%

Effect of Phenobarbital on the Pharmacokinetics of Rutaecarpine and its Metabolite in Rats

Kim¹,

Lee²,

Seo³

et al. 2008

Biomolecules and Therapeutics

View full text Add to dashboard Cite

− To investigate the possible interaction between rutaecarpine and phenobarbital in rats, phenobarbital in saline at 80 mg/kg was given ip to male SD rats for 3 consecutive days. Saline was given to control animals. One day after phenobarbital pre-treatment, rutaecarpine at 16 mg/kg was administered through penile vein. Blood was collected and analyzed by using HPLC. The pharmacokinetic parameters were determined with the non-compartmental model. Pre-treatment with phenobarbital significantly altered the pharmacokinetic profiles of rutaecarpine and its metabolite, 10-hydroxyrutaecarpine. The AUC of rutaecarpine was reduced to approximately 50% of control and the plasma half-life of rutaecarpine was significantly shortened when compared with control. In addition, the Cmax of 10-hydroxyrutaecarpine was increased approximately 160% of control. The AUC and the plasma half-life of 10-hydroxyrutaecarpine were decreased to 76.9% of control and to 82.7 min from 175.9 min, respectively. The results suggested that phenobarbital might accelerate the metabolism of rutaecarpine, thereby changing the pharmacokinetic parameters of rutaecarpine in male SD rats.

show abstract

“…28 Due to this interaction at P450 sites, CMT has been associated with many drug-drug interactions involving the inhibition of CYP2D6 and other P450 isozymes. [29][30][31] When CMT is combined with MA, levels of both MA and AMP were significantly higher in the rat CNS compared to rats that did not receive CMT. 32 CMT is metabolized by P450 enzymes to its major metabolite, an S-oxide.…”

mentioning

confidence: 99%

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Wallace¹,

Crosswy²

2017

Toxicol Forensic Med Open J

View full text Add to dashboard Cite

Citation ResearchAbSTRACT Aim: To determine the interaction of over-the-counter (OTC) and illicit psychostimulants at the cytochrome P450 enzyme, CYP2D6. CYP2D6 is responsible for 20% of hepatic Phase I metabolism and is a site of drug-drug interactions, leading to increased drug toxicity. Materials and Methods: We examined the effects the OTC drugs; 1) the prototype H 2 -antagonist cimetidine (CMT) and 2) the opioid agonist cough suppressant dextromethorphan (DEX); as well as two scheduled drugs, methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA) for their ability to interfere with CYP2D6 activity. Assays with human CYP2D6 determined the inhibitory potential (IC 50 ) of each drug. Kinetic analysis (V max and K m ) was accomplished using rodent hepatic microsomes. Results: Maximum inhibition of CYP2D6 activity following exposure to CMT+MDMA was significantly reduced 75-85% compared to quinidine (control) values. These data showed inhibitory effects in CYP2D6 activity in each compound tested. Alterations in CYP2D6 activity may result in complex drug-drug interactions leading to elevated plasma levels of drugs and increased risk for toxicity. Assays using rat CYP2D2 demonstrated V max elevations in the CMT group (493%) compared to control (naïve, no treatment) values (19.9±5.1 pmol/mg protein/ min). The K m was increased 218% in CMT compared to controls (3.1±0.5 μM). Collectively, all MA challenged groups exhibited increases in total enzyme [V max ; 280-490%] and affinity [K m ; 165-220%] values compared to the control group. The increase in both V max and K m suggests that the low affinity/high capacity CYP2D2 isoform is upregulated. Conclusion: Our findings suggest that in vivo, MA acts as a CYP2D2-inducer, which will lead to altered secondary drug metabolism, increasing the risk of drug-related toxicity. Coupled with the ability of CMT and DEX to interfere with MA metabolism, a complex drug-drug interaction is possible, leading to increased toxicity. Our findings substantiate the hypothesis that the combination of illicit and OTC drugs could result in complex drug-drug interactions increasing the risk for severe drug-related toxicity.

show abstract

Effect of cimetidine and phenobarbital on metabolite kinetics of omeprazole in rats

Cited by 12 publications

References 19 publications

Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice

Phenobarbital Treatment at a Neonatal Age Results in Decreased Efficacy of Omeprazole in Adult Mice

Effect of Phenobarbital on the Pharmacokinetics of Rutaecarpine and its Metabolite in Rats

Interactions between Over-the-Counter and Illicit Drugs Utilizing Cytochrome P450 Metabolism: Potential for Exacerbation of Pharmacological Response

Contact Info

Product

Resources

About