Atorvastatin does not Produce a Clinically Significant Effect on the Pharmacokinetics of Terfenadine

Stern, Robert L.; Smithers, Jacquelyn A.; Olson, Stephen C.

doi:10.1002/j.1552-4604.1998.tb04816.x

Cited by 20 publications

(7 citation statements)

References 10 publications

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“…The area under the curve (AUC) of verapamil was increased and the ratio of norverpamil : verapamil AUCs was decreased with concurrent 40 mg atorvastatin dosing indicating the inhibition of both MDR1 and CYP3A4 . Atorvastatin 80 mg co‐administration for 7 days increased terfenadine AUC . The AUC of norethisterone and ethinylestradiol were increased with 22 day administration of 40 mg atorvastatin (Lipitor Summary of Product Characteristics).…”

Section: Discussionmentioning

confidence: 99%

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The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Hukkanen

Puurunen

Hyötyläinen

et al. 2015

Brit J Clinical Pharma

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AIMSAtorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C). METHODSIn this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day À1 (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls. RESULTSTreatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference -0.0595, -0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin -0.032, placebo 0.0055, P = 0.020, 95% CI of the difference -0.069, -0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change. CONCLUSIONSThe results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Atorvastatin is known as a CYP3A4 inhibitor but it is also a PXR-activating inducer of CYP3A4 in vitro. The in vivo relevance of PXR activation is unknown.• The cholesterol metabolite 4β-hydroxycholesterol (4βHC) is a convenient marker of CYP3A4 activity but its use has not been evaluated in situations with changing cholesterol concentrations. WHAT THIS STUDY ADDS• No induction of CYP3A4 by atorvastatin was detected. Atorvastatin is an inhibitor of CYP3A4 activity.• The ratio of 4βHC to cholesterol is a feasible index of CYP3A4 activity also when cholesterol concentrations have changed.• Atorvastatin treatment reduces the concentrations of the oxysterols 4βHC and 5α,6α-epoxycholesterol.

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Section: Discussionmentioning

confidence: 99%

“…The Pearson correlation coefficients of total cholesterol and oxysterols at the baseline (n = 29) 7 days increased terfenadine AUC [29]. The AUC of norethisterone and ethinylestradiol were increased with 22 day administration of 40 mg atorvastatin (Lipitor Summary of Product Characteristics).…”

Section: Tablementioning

confidence: 97%

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Hukkanen

Puurunen

Hyötyläinen

et al. 2015

Brit J Clinical Pharma

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“…Atorvastatin is a potent inhibitor of OATP1B1 in vitro (IC 50 = 0.87 μmol/l), 17 but both atorvastatin and its lactone form also inhibit CYP3A4 (IC 50 74.6 μmol/l and 5.6 μmol/l, respectively) and CYP2C8 (IC 50 38.4 μmol/l and 28.8 μmol/l, respectively) in vitro 27 , 28 . Atorvastatin impairs the ability of clopidogrel to inhibit platelet aggregation (possibly because of the reduced formation of the active metabolite of clopidogrel) and increases the AUC of the CYP3A4 substrates midazolam and terfenadine by ∼40% 29 , 30 , 31 . In this study, atorvastatin showed no effect on the formation of the M1, M2, and M4 metabolites of repaglinide, thereby indicating that atorvastatin is not a potent inhibitor of CYP3A4 or CYP2C8 in vivo .…”

Section: Discussionmentioning

confidence: 99%

Effects of Gemfibrozil and Atorvastatin on the Pharmacokinetics of Repaglinide in Relation to SLCO1B1 Polymorphism

Kalliokoski

Backman

Kurkinen

et al. 2008

Clin Pharmacol Ther

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In a randomized crossover study, 24 SLCO181-genotyped healthy volunteers were given daily doses of 1,200 mg gemfibrozil, 40 mg atorvastatin, or placebo, followed by 0.25 mg of repaglinide on day 3. The mean increase in the repaglinide area under the plasma concentration-time curve from 0 h to infinity (AUC(0-infinity)) produced by gemfibrozil was larger in individuals with the SLCO1B1 c.521CC genotype (n = 6) than in those with the c.521TC (n = 6) and c.521TT (n = 12) genotypes, by factors of 1.56 (P = 0.004) and 1.54 (P = 0.002), respectively. Gemfibrozil prolonged the repaglinide elimination half-life 1.43 times more in the c.521 CC group than in the c.521TT group (P = 0.047), but no differences were seen in the effects on peak plasma concentration (C(max)). While on gemfibrozil, the minimum blood glucose concentration after repaglinide intake was 19% lower in the c.521CC participants than in the c.521TT participants (P = 0.009). In the c.521TT group, atorvastatin intake had the effect of increasing repaglinide Cmax and AUC(0-infinity) by41% (P = 0.001) and 18% (P = 0.033), respectively. In conclusion, the extent of gemfibrozil-repaglinide interaction depends on SLCO1B1 genotype. Atorvastatin raises plasma repaglinide concentrations, probably by inhibiting organic anion transporting polypeptide 1B1 (OATP1B1).

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“…The clearance of the CYP3A4 substrate midazolam administered intravenously has been 30% smaller in patients receiving concurrent atorvastatin therapy than in control patients 145 . In another study atorvastatin slightly increased the AUC of terfenadine (by 35%), another well‐known CYP3A4 substrate 146 …”

Section: Other Interactions Of Lipid‐lowering Drugsmentioning

confidence: 97%

“…145 In another study atorvastatin slightly increased the AUC of terfenadine (by 35%), another well-known CYP3A4 substrate. 146 High doses of some statins (eg, simvastatin and atorvastatin) can slightly increase the plasma concentrations of digoxin (up to 20%), possibly by inhibiting its MDR1-mediated efflux. 77,147 The clinical significance of these statin-digoxin interactions is limited.…”

Section: Other Interactions Of Lipid-lowering Drugsmentioning

confidence: 99%

Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance

Neuvonen

Niemi

Backman

2006

Clinical Pharmacology & Therapeutics

736

588

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Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic disease. The benefits of statins are well documented. However, lipid-lowering drugs may cause myopathy, even rhabdomyolysis, the risk of which is increased by certain interactions. Simvastatin, lovastatin, and atorvastatin are metabolized by cytochrome P450 (CYP) 3A4 (simvastatin acid is also metabolized by CYP2C8); their plasma concentrations and risk of myotoxicity are greatly increased by strong inhibitors of CYP3A4 (eg, itraconazole and ritonavir). Weak or moderately potent CYP3A4 inhibitors (eg, verapamil and diltiazem) can be used cautiously with small doses of CYP3A4-dependent statins. Cerivastatin is metabolized by CYP2C8 and CYP3A4, and fluvastatin is metabolized by CYP2C9. The exposure to fluvastatin is increased by less than 2-fold by inhibitors of CYP2C9. Pravastatin, rosuvastatin, and pitavastatin are excreted mainly unchanged, and their plasma concentrations are not significantly increased by pure CYP3A4 inhibitors. Cyclosporine (INN, ciclosporin) inhibits CYP3A4, P-glycoprotein (multidrug resistance protein 1), organic anion transporting polypeptide 1B1 (OATP1B1), and some other hepatic uptake transporters. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. These effects of cyclosporine and gemfibrozil explain the increased plasma statin concentrations and, together with pharmacodynamic factors, the increased risk of myotoxicity when coadministered with statins. Inhibitors of OATP1B1 may decrease the benefit/risk ratio of statins by interfering with their entry into hepatocytes, the site of action. Lipid-lowering drugs can be involved also in other interactions, including those between enzyme inducers and CYP3A4 substrate statins, as well as those between gemfibrozil and CYP2C8 substrate antidiabetics. Knowledge of the pharmacokinetic and pharmacodynamic properties of lipid-lowering drugs and their interaction mechanisms helps to avoid adverse interactions, without compromising therapeutic benefits.

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Atorvastatin does not Produce a Clinically Significant Effect on the Pharmacokinetics of Terfenadine

Cited by 20 publications

References 10 publications

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Effects of Gemfibrozil and Atorvastatin on the Pharmacokinetics of Repaglinide in Relation to SLCO1B1 Polymorphism

Drug interactions with lipid-lowering drugs: Mechanisms and clinical relevance

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