Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil

Tracy, Timothy S.; Korzekwa, Kenneth R.; Gonzalez, Frank J.; Wainer, Irving W.

doi:10.1046/j.1365-2125.1999.00923.x

Cited by 152 publications

(122 citation statements)

References 14 publications

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“…5, A-F, Ⅺ); however, in the ileum, simulated permeability of quinidine in the lower concentration range deviated slightly from the measured permeability. One of the plausible explanations for this inconsistency is that, because several cytochrome P-450 enzymes were reported to be expressed in the intestinal epithelial layer, cytochrome P-450-mediated metabolism of drugs during the intestinal absorption process might affect the permeability measured by the in situ single-pass perfusion method (Ching et al, 1995;Tracy et al, 1999;Galetin and Houston, 2006). In addition, the effects of other ABC transporters, such as breast cancer resistance protein and multidrug resistanceassociated protein 2, are possible factors in the deviation (Englund et al, 2006;Han and Sugiyama, 2006).…”

Section: Downloaded Frommentioning

confidence: 99%

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Shirasaka¹,

Masaoka²,

Kataoka³

et al. 2008

Drug Metab Dispos

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ABSTRACT:In a previous study, the concentration-dependent permeability of P-glycoprotein (P-gp) substrate drugs, quinidine, verapamil, and vinblastine, in several cell monolayers with different levels of P-gp expression was analyzed kinetically to obtain fundamental parameters for P-gp-mediated transport, V max and K m(app) values. Both V max and K m(app) values of each drug were found to show linear correlations with the expression level of P-gp. These findings imply the possibility of estimating the V max and K m(app) values of P-gp substrate drugs in the in vivo intestinal membrane on the basis of the P-gp expression level. In the present study, concentrationdependent drug permeability to the rat small intestines (upper jejunum and ileum) was simulated on the basis of V max and K m(app) values of each drug estimated from the P-gp expression level in the rat small intestines. To validate the predictability of these procedures, drug permeability in the rat small intestines was measured by the in situ single-pass perfusion method. It was confirmed that simulated permeability of each drug in the rat jejunum and ileum corresponded well with permeability measured by the in situ single-pass perfusion method. This study clearly demonstrated the potential to estimate the permeability of P-gp substrate drugs in the human intestine from its P-gp expression level and thus the possibility to predict the oral absorption of those drugs.P-glycoprotein (P-gp), one of the most important efflux transporters in the field of biopharmacy, is an ATP-binding cassette (ABC) transporter encoded by the multidrug resistance 1 gene (MDR1/ABCB1). P-gp is expressed not only in cancer cells but also in many normal tissues (Loo and Clarke, 1999). So far, many reports have described the effects of P-gp on the pharmacokinetic profiles of clinically important drugs, by denaturing absorption, distribution, and excretion. For example, P-gp located in the apical domain of the enterocytes of the gastrointestinal tract limits the uptake and absorption of its substrate drugs after oral administration (Hunter and Hirst, 1997;Meijer et al., 1997;Jonker et al., 1999). Because of the great impact of P-gp on the pharmacokinetic profiles of a variety of drugs, various in vitro experimental techniques are now used to identify the compounds subjected to P-gp-mediated efflux (Kim et al., 1998;Polli et al., 1999Polli et al., , 2001Susanto and Benet, 2002; Shirasaka et al., 2006a,b). However, it is still difficult to quantitatively predict the effect of P-gp on in vivo intestinal absorption of such drugs.In a previous study, we measured the apical (AP) to basal (BL) absorptive permeability of P-gp substrate drugs in several cultured cell monolayers with different expression levels of P-gp (Shirasaka et al., 2008). In all cell monolayers, AP to BL permeability of P-gp substrate drugs showed a sigmoid-type relation to their donor (AP) concentration and reached a maximal value at the higher concentration range because of the saturation of P-gp-mediated efflux. Con...

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Section: Downloaded Frommentioning

confidence: 99%

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Shirasaka¹,

Masaoka²,

Kataoka³

et al. 2008

Drug Metab Dispos

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“…Human CYP3A4 and rat CYP3A1 have 73% protein homology (Lewis, 1996). It was reported that CYP3A4 was mainly responsible for the metabolism of verapamil in humans, whereas CYP3A1/2 govern the metabolism of verapamil in rats (Tracy et al, 1999;Choi and Burm, 2008;Hanada et al, 2008). Verapamil undergoes extensive first-pass metabolism, with low oral bioavailability (10 -20%) in various animal species (Schomerus et al, 1976;Woodcock et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

Hu¹,

Xie²,

Liu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The aim of this study was to report the effect of diabetes mellitus on the pharmacokinetics of verapamil in a route-dependent manner. Diabetes in rats was induced by streptozotocin. Plasma concentrations of verapamil and its metabolite, norverapamil, were measured after oral (10 mg/kg) or intravenous (1 mg/kg) administration. The concentrations of verapamil in portal plasma after oral administration were also determined. Norverapamil formation was used for assessing CYP3A activity in hepatic and intestinal microsomes of diabetic rats. The protein levels of CYP3A1 and CYP3A2 in liver and intestine were measured by Western blot. It was found that diabetes significantly increased the plasma concentration of verapamil and norverapamil after oral administration, which resulted in a 74% increase in the area under the concentration-time curve (AUC) of verapamil, but the ratio of AUC (norverapamil) /AUC (verapamil) was significantly decreased by 38%. In contrast, diabetes significantly decreased the AUC of verapamil by 22% after intravenous administration. Diabetes also resulted in increased AUC of verapamil in portal vein by 3.8-fold compared with that in control rats. The absolute bioavailability of verapamil was higher than that of control rats. An in vitro study showed that increased CYP3A activity in the hepatic microsome and decreased CYP3A activity in the intestinal microsome were accompanied by an increase and decrease in the protein expression of CYP3A1/2 in liver and intestine of diabetic rats, respectively. In conclusion, diabetes mellitus revealed a tissue-specific effect on CYP3A activity and expression (induced in liver and inhibited in intestine), resulting in opposite pharmacokinetic behaviors of verapamil after oral and intravenous administration to diabetic rats.

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“…It is mainly metabolized via N-methylation and para-hydroxylation by CYP2C8 through phase I metabolism, and to a lesser extent by CYP2C9 (Baldwin et al, 1999). Recently, the contributions made by CYP2C8 to the metabolisms of cerivastatin, paclitaxel, repaglinide, and verapamil have been studied Tracy et al, 1999;Mück, 2000;Niemi et al, 2003a). The pharmacokinetics of rosiglitazone is known to be altered when it is co-administered with other drugs which were involved with the induction or inhibition of CYP2C8, such as, gemfibrozil, trimethoprim and rifampin (Tracy et al, 1999;Park et al, 2004;Hruska et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the contributions made by CYP2C8 to the metabolisms of cerivastatin, paclitaxel, repaglinide, and verapamil have been studied Tracy et al, 1999;Mück, 2000;Niemi et al, 2003a). The pharmacokinetics of rosiglitazone is known to be altered when it is co-administered with other drugs which were involved with the induction or inhibition of CYP2C8, such as, gemfibrozil, trimethoprim and rifampin (Tracy et al, 1999;Park et al, 2004;Hruska et al, 2005). Gemfibrozil, which has an inhibitory effect on CYP2C8, was found to increase the AUC of rosiglitazone (maximally 2.8-fold) and to prolong its elimination half-life (maximally 7.6 h) (Niemi et al, 2003b).…”

Section: Introductionmentioning

confidence: 99%

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

Kim¹,

Kim²,

Um³

et al. 2009

Biomolecules and Therapeutics

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-Rosiglitazone maleate (RGM) is widely used for improving insulin resistance. RGM is a moderate inhibitor of cytochrome P450 2C8 (CYP2C8) and is also mainly metabolized by CYP2C8. The aim of this study was to determine whether the effect of RGM on CYP2C8 is altered by co-treatment with other drugs, and whether amlodipine camsylate (AC) changes the pharmacokinetics (PK) of RGM. Of the 11 drugs that are likely to be co-administered with RGM in diabetic patients, seven drugs lowered the IC 50 value of RGM on CYP2C8 by more than 80%. In vitro CYP2C8 inhibitory assays of RGM in combination with drugs of interest showed that the IC50 of RGM was decreased by 98.9% by AC. In a pharmacokinetic study, Sprague-Dawley (SD) rats were orally administered 1 mg/kg of RGM following by single or 10-consecutive daily administrations of 1.5 mg/kg/day of AC. No significant changes in the pharmacokinetic parameters of RGM were observed after a single administration of AC, but the AUC and Cmax values of RGM were significantly reduced by 36% and 31%, respectively, by multiple administrations of AC. In conclusion, RGM was found to be affected by AC by in vitro CYP2C8 inhibition testing, and multiple dosing of AC appreciably changed the pharmacokinetics of RGM. These findings suggest that a drug interaction exists between AC and RGM.

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Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil

Cited by 152 publications

References 14 publications

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Scaling of in Vitro Membrane Permeability to Predict P-glycoprotein-Mediated Drug Absorption in Vivo

Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

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