Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous omeprazole in rats

Lee, Dae Y.; Shin, Hyun S; Bae, Soo Kyung; Lee, Myung G.

doi:10.1002/bdd.502

Cited by 31 publications

(30 citation statements)

References 38 publications

(60 reference statements)

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“…The result revealed that DEX weakly induced CYP3A1/2 mRNA expression following the incubation of 6 h, which was different from those reported in literatures. 22) PXT and DEX didn't affect CYP3A1/2 mRNA expression after culturing for 45 min. However, after incubation for 6 h in the presence of PXT (4.0, 8.0 µg/mL), CYP3A1 mRNA expression level was decreased to 87 and 80% of that in control, and CYP3A2 mRNA expression level was decreased to 89 and 85% of that in control, respectively.…”

Section: Discussionmentioning

confidence: 84%

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Zhang

Zeng

et al. 2015

Biological & Pharmaceutical Bulletin

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In our previous study, panaxytriol (PXT) was shown to enhance midazolam (MDZ) 1′-hydroxylation significantly but to inhibit MDZ 4-hydroxylation. To explore the underlying mechanism, we investigated the effects of PXT on cytochrome P450 3A (CYP3A)-mediated MDZ metabolic pathways using rat liver microsomes (RLM), human liver microsomes (HLM), and rat primary hepatocytes. In the presence of PXT, the V max of 4-OH MDZ decreased from 0.72 to 0.51 nmol/min·mg pro in RLM and from 0.32 to 0.12 nmol/ min·mg pro in HLM, and the K m value increased from 5.12 to 7.26 µM in RLM and from 27.87 to 32.80 µM in HLM. But the presence of PXT reduced the K m and increased the V max values of MDZ 1′-hydroxylation in RLM and HLM. Interestingly, the differential effect of PXT on MDZ 4-hydroxylation and 1′-hydroxylation was also observed in primary rat hepatocytes after 45-min culture. PXT did not affect the expression levels of CYP3A1/2 mRNA in rat hepatocytes. With extension of the culture time to 6 h, however, PXT significantly inhibited both MDZ 4-hydroxylation and 1′-hydroxylation, and the expression level of CYP3A1/2 mRNA was decreased to 87% and 80% (CYP3A1) and to 89% and 85% (CYP3A2) of those in controls in the presence of PXT 4.0 and 8.0 µg/mL, respectively. These results suggest that PXT could activate MDZ 1′-hydroxylation but inhibit MDZ 4-hydroxylation by changing the CYP3A enzyme affinity and metabolic rate after a shortterm intervention. However, long-term treatment with PXT could inhibit both the 4-hydroxylation and 1′-hydroxylation of MDZ by downregulating CYP3A1/2 mRNA expression.Key words panaxytriol; midazolam hydroxylation metabolism; cytochrome P450 3A; differential effect mechanism Cytochrome P450 (CYP450) is a superfamily of hemeproteins that involved in the biotransformation of the majority of clinical drugs. The inhibition or induction effect of clinical drugs on CYP450 is considered as one of the important factors leading to potential drug-drug interactions.1-3) CYP3A4 is one of the primary CYP450 enzymes in human liver and catalyzes the metabolism of more than 50% of clinical drugs including terfenadine, theophylline and astemizole, etc. Midazolam (MDZ) is the specific substrate of CYP3A4 enzyme and is mainly metabolized to 4-hydroxymidazolam (4-OH MDZ) and 1′-hydroxymidazolam (1′-OH MDZ) by combining with the two different sites of CYP3A4 enzyme active center.4,5) Therefore, the formation of the two metabolites are often simultaneously quantified for the assessment of CYP3A4 activity.Traditional Chinese medicine is widely used in clinical practice in China because of the advantages of good curative effect and less adverse reaction. The incidence of Chinese medicine and chemical medicine interactions significantly increased as the widely using of Chinese medicine, and the change of CYP450 enzyme activity is the principal cause resulting in drug metabolic interactions. 6,7) As a well known study, salvia extract exhibited a marked inhibition effect on the expression of CYP3A4 and CYP1A2 mRNA in HepG2, and high...

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Section: Discussionmentioning

confidence: 84%

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Zhang

Zeng

et al. 2015

Biological & Pharmaceutical Bulletin

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“…The largest E (2) value is found in conformer III, followed by conformer II and, finally, conformer I.…”

mentioning

confidence: 93%

“…While the strength of the interaction due the electron delocalization, E (2) , is estimated by the second-order perturbation…”

Section: Methodsmentioning

confidence: 99%

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Looking for the interactions between omeprazole and amoxicillin in a disordered phase. An experimental and theoretical study

Russo

Sancho

Silva

et al. 2016

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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In this paper, co-grinding mixtures of omeprazole-amoxicillin trihydrate (CGM samples) and omeprazole-anhydrous amoxicillin (CGMa samples) at 3:7, 1:1 and 7:3 molar ratios, respectively, were studied with the aim of obtaining a co-amorphous system and determining the potential intermolecular interactions. These systems were fully characterized by differential scanning calorimetry (DSC), FT-infrared spectroscopy (FTIR), X-ray powder diffraction (PXRD), scanning electron microscopy (SEM) and solid state Nuclear Magnetic Resonance (ssNMR). The co-grinding process was not useful to get a co-amorphous system but it led to obtaining the 1:1 CGMa disordered phase. Moreover, in this system both FTIR and ssNMR A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 analysis strongly suggest intermolecular interactions between the sulfoxide group of omeprazole and the primary amine of amoxicillin anhydrous. The solubility measurements were performed in simulated gastric fluid (SGF) to prove the effect of the co-grinding process.Complementarily, we carried out density functional theory calculations (DFT) followed by quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses in order to shed some light on the principles that guide the possible formation of heterodimers at the molecular level, which are supported by spectroscopic experimental findings.

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“…The drug has greater antisecretory activity than histamine H 2 -receptor antagonists and has been used widely in the treatment of peptic ulcer, efflux oesophagitis and Zollinger--Ellison syndrome [1]. Lee et al [2] reported that omeprazole is metabolized primarily via hepatic microsomal cytochrome P450 (CYP) 1A1/2, 2D1 and 3A1/2 (not via CYP2B1/2, 2C11 and 2E1) in male Sprague-Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

Lee

Jung

Kim

et al. 2009

Biopharm & Drug Disp

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It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl(nr) was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first-pass effect in NARs than in the controls.

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Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous omeprazole in rats

Cited by 31 publications

References 38 publications

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Mechanism of Action of Panaxytriol on Midazolam 1′-Hydroxylation and 4-Hydroxylation Mediated by CYP3A in Liver Microsomes and Rat Primary Hepatocytes

Looking for the interactions between omeprazole and amoxicillin in a disordered phase. An experimental and theoretical study

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

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