The interaction of diltiazem with lovastatin and pravastatin.
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 (Cmax) from 6 +/- 2 to 26 +/- 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, Cmax, 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.


CONCLUSIONS
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.
Azie
N E
NE
Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Brater
D C
DC
Becker
P A
PA
Jones
D R
DR
Hall
S D
SD
D000284:Administration, Oral; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008148:Lovastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D017035:Pravastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values
D000924:Anticholesteremic Agents; D002317:Cardiovascular Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D017035:Pravastatin