The interaction of diltiazem with lovastatin and pravastatin

Nkechi E. Azie, D. Craig Brater, Paula A. Becker, David R. Jones, Stephen D. Hall

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Background: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. Methods: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. Results: Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 ± 1525 ng/ml/min (mean ± SD) to 12886 ± 6558 ng/ml/min and maximum serum concentration (C(max)) from 6 ± 2 to 26 ± 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, C(max), or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 ± 58 ng/ml) and pravastatin (110 ± 30 ng/ml) study arms. Conclusion: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3- methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.

Original languageEnglish (US)
Pages (from-to)369-377
Number of pages9
JournalClinical Pharmacology and Therapeutics
Volume64
Issue number4
DOIs
StatePublished - Oct 1 1998

Fingerprint

Pravastatin
Lovastatin
Diltiazem
Cytochromes
fluvastatin
Serum
Area Under Curve
Half-Life
Simvastatin
Cross-Over Studies
Cytochrome P-450 Enzyme System
Healthy Volunteers
Oxidoreductases
Cholesterol
Enzymes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Azie, N. E., Brater, D. C., Becker, P. A., Jones, D. R., & Hall, S. D. (1998). The interaction of diltiazem with lovastatin and pravastatin. Clinical Pharmacology and Therapeutics, 64(4), 369-377. https://doi.org/10.1016/S0009-9236(98)90067-4

The interaction of diltiazem with lovastatin and pravastatin. / Azie, Nkechi E.; Brater, D. Craig; Becker, Paula A.; Jones, David R.; Hall, Stephen D.

In: Clinical Pharmacology and Therapeutics, Vol. 64, No. 4, 01.10.1998, p. 369-377.

Research output: Contribution to journalArticle

Azie, NE, Brater, DC, Becker, PA, Jones, DR & Hall, SD 1998, 'The interaction of diltiazem with lovastatin and pravastatin', Clinical Pharmacology and Therapeutics, vol. 64, no. 4, pp. 369-377. https://doi.org/10.1016/S0009-9236(98)90067-4
Azie, Nkechi E. ; Brater, D. Craig ; Becker, Paula A. ; Jones, David R. ; Hall, Stephen D. / The interaction of diltiazem with lovastatin and pravastatin. In: Clinical Pharmacology and Therapeutics. 1998 ; Vol. 64, No. 4. pp. 369-377.
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abstract = "Background: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. Methods: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. Results: Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 ± 1525 ng/ml/min (mean ± SD) to 12886 ± 6558 ng/ml/min and maximum serum concentration (C(max)) from 6 ± 2 to 26 ± 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, C(max), or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 ± 58 ng/ml) and pravastatin (110 ± 30 ng/ml) study arms. Conclusion: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3- methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.",
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AU - Brater, D. Craig

AU - Becker, Paula A.

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AU - Hall, Stephen D.

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N2 - Background: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. Methods: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. Results: Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 ± 1525 ng/ml/min (mean ± SD) to 12886 ± 6558 ng/ml/min and maximum serum concentration (C(max)) from 6 ± 2 to 26 ± 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, C(max), or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 ± 58 ng/ml) and pravastatin (110 ± 30 ng/ml) study arms. Conclusion: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3- methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.

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