the interaction of diltiazem with lovastatin and pravastatin*

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 (I’ < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 + 1525 ng/ml/min (mean + SD) to 12886 f 6558 ng/ml/min and maximum serum concentration (C,,) f rom 6 f 2 to 26 3 9 rig/ml but did not influence the elimination half- life. Diltiazem did not affect the oral AUC, C,,, or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 + 58 rig/ml) and pravastatin (110 c 30 rig/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-hydroxy3-methylglutaryl- coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin. (Clin Pharmacol Ther 1998;64:369-77.)

Nkechi E. Azie, MD, D. Craig Brater, MD, Paula A. Becker, RN, David R Jones, PhD, and Stephen D. Hall, PhD Indianapolis, Ind

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, such as lovastatin and pravastatin, represent a class of drugs that have potent, dose-dependent, low-density lipoprotein cholesterol-lowering effects and are generally well toler- ated. The enzyme HMG-CoA reductase catalyzes the

From the Division of Clinical Pharmacology, Department of Medi- cine, Indiana University School of Medicine.

Supported by grants AGl3718, GM08425, and GCRC MO1 RR00750 from the National Institutes of Health (Bethesda, Md). Analytical support provided by Bristol-Myers Squibb Pharmaceu- ticals (Princeton, NJ).

Received for publication Feb 23, 1998; accepted July 17, 1998. Reprint requests: Stephen D. Hall, PhD, Wishard Memorial Hospi-

tal, West Outpatient Bldg 320, 1001 West Tenth St, Indianapolis, IN 46202.2879. E-mail: [email protected]

Copyright 0 1998 by Mosby, Inc. 0009-9236/98/$5.00 + 0 13/l/93149

conversion of HMG-CoA to mevalonic acid, which is the rate-limiting step in the biosynthesis of cholesterol. These drugs are widely used, exhibit a plateauing dose- response curve at recommended doses, and have been shown repeatedly to be beneficial in the prevention of initial and subsequent ischemic events in patients with coronary heart disease risk and to reduce mortality in those who have already had a myocardial infarction.]-s Pravastatin and lovastatin are structurally similar (Fig- ure 1) but with different pharmacokinetic properties.6.7 With use of ex vivo assays it has been shown that lovastatin accounts for 25% of the inhibition of HMG-CoA reductase activity in plasma, with the remainder presumably attributable to one or more active metabolites.s9 In turn, these metabolites appear to be formed by cytochrome P450 (CUP) 3A4, a major determinant of lovastatin clearance and bioavailability.8 In contrast, the concentration of pravastatin alone accounts for 75%

369

370 Azie et al. CLINICAL PHARMACOLOGY & THERAPEUTICS

OCTOBER 1998

*

CH, Non-GYP

Dependent

Lovastatin

CYPBA Dependent

6’ p - Hydroxy-Lovartatin 3” - Hydroxy-Lovastatin 6 - Exomethylene-Lovastatin

Figure 1. Structures of pravastatin, lovastatin, and the hydroxy acid form of lovastatin.

of HMG-CoA reductase inhibition in plasma.9 Metab- olism is only a minor route of pravastatin elimination, and CYP3A enzymes do not contribute significantly to pravastatin clearance or bioavailability. lo-l2

Diltiazem has been shown to be effective for the clinical management of stable angina pectoris, supraven- tricular arrhythmias, and hypertension. As a heart rate-lowering calcium antagonist, it has been shown to be beneficial in patients with coronary artery disease, especially after non-Q wave myocardial infarction.13 Many of these patients also need concurrent lipid- lowering agents, and HMG-CoA reductase inhibitors are commonly used. It is well known that CYP3A enzymes are central to many drug interactions and numerous inhibitors of this enzyme have been identified, including ketoconazole, erythromycin, and some calcium antagonists, including diltiazem and verap- ami1.14J5 Diltiazem has been reported to interact with several CYP3A substrates, including terfenadine, car- bamazepine, cyclosporine (INN, ciclosporin), and midazolam.16,17 It follows that in the subset of patients who require diltiazem and an HMG-CoA reductase inhibitor metabolized by CYP3A, the potential for a drug interaction exists. One of the major reasons for intolerance and discontinuation of HMG-CoA reductase inhibitor therapy is the occurrence of a drug-drug interaction. l 8

Rhabdomyolysis is a rare side effect of HMG-CoA reductase inhibitor monotherapy and appears to be dose related.3 However, the risk of development of rhabdomyolysis is considerably increased with concurrent administration of CYP3A inhibitors, such as cyclosporine, with lovastatin.is-24 It is therefore possible that coadministration of other CYP3A inhibitors

will affect the risk to benefit ratio of lovastatin by diminishing the formation of the active metabolite and increasing the serum concentration of the parent com- pound, which may cause the myopathy. Pravastatin would not be expected to exhibit such an interaction. We studied the effect of coadministration of diltiazem on lovastatin and pravastatin pharmacokinetics to test the hypothesis that a substantial interaction would occur with lovastatin but not with pravastatin.

METHODS Clinical protocol

Ten healthy volunteers (5 men and 5 women) provided written informed consent approved by the insti- tutional review board of Indiana University (Indianapo- lis, Ind). All volunteers were within 15% of ideal body weight (mean f SD weight, 79.5 f 16.2 kg); mean age was 32 f 5 years (Table I). The history and physical examination, ECG, and hematologic and biochemical tests showed no abnormal findings. None of the volunteers had histories of smoking or alcohol abuse, and none of the women were taking oral contraceptives, Alcohol and medications were not allowed within 7 days of the study or during the study. No study drug was allowed for 30 days before the study. Subjects abstained from caffeine-containing beverages for 2 days before and throughout the study.

The study was conducted on an outpatient basis except for the lovastatin or pravastatin dosing days. A randomized, 4-way crossover design was applied. The 4 arms of the study were (1) administration of a single dose of 20 mg lovastatin orally, (2) administration of a single dose of 20 mg pravastatin orally, (3) administration of a single dose of lovastatin orally after 2 weeks

CLINICAL PHARMACOLOGY & THERAPt.UTICS VOLUME 64, NUMBER 4 Azie et al. 371

Table I. Steady-state and trough concentrations of diltiazem for the lovastatin and pravastatin study arms

Subject No. Gender Weight

(kg)

Lovastatin Pravastatin

Diltiazem C,, Diltiazem trough Diltiazem C,, Diltiazem trough (ng/mL) concentration (ng/mL) (n&-G concentration (n,g/mLj

1 Female 70.1 104 97 2 Female 62.1 132 83 3 Female 54.2 297 84 4 Female 77.0 99 134 5 Female 77.0 119 53 6 Male 93.5 132 65 7 Male 106.0 91 68 8 Male 88.4 88 90 9 Male 100.0 98 41

10 Male 66.3 138 94

Mean 79.5 130 81 110 84 SD 16.2 58.4 24.9 30.4 20.4

110 82 115 69 182 III 101 116 123 66

82 XX 81 63 67 82

125 55 115 106

C,,, Steady-state concentration.

of 120 mg diltiazem (Cardizem SR) twice a day, and (4) administration of a single dose of pravastatin orally after 2 weeks of 120 mg diltiazem (Cardizem SR) twice a day. Each arm was separated by a minimum of 2 weeks.

Blood samples for determination of lovastatin and pravastatin serum concentrations were obtained at 0, %, %, %, 1, l%, 2, 21/2, 3, 4, 6, 8, 12, and 24 hours after dosing. The final dose of diltiazem was administered 1 hour before the lovastatin or pravastatin dose and samples were obtained at times 0, 1, 2, 5, 13, and 25 hours for determination of diltiazem concentrations. The serum samples were stored at -70°C until assayed.

Drug assays Diltiuzem. Diltiazem concentrations in serum sam-

ples were quantified by an HPLC method that was a modification of that described by Yeung et al.25 Dilti- azem was resolved from the internal standard, imipramine, with a mobile phase of 40% buffer (0.01 mol/L sodium acetate, 0.01% tetraethylammonium pH 6.3, with glacial acetic acid), 2% tetrahydrofuran, 36% methanol, and 22% acetonitrile. The mobile phase flow was set at 1.5 mL/min through a 5 pm Cs column (25 cm x 3.5 mm, Ultrasphere, Beckman Instruments, San Ramon, Calif) with detection by ultraviolet absorbance at a wavelength of 237 nm. A 500 pL aliquot of serum was extracted into 5 mL hexane after basification with 200 pL sodium bicarbonate (IO%, pH 9). Standard curves were prepared over a range of concentrations from 10 to 1000 ng/mL. Quantification was achieved by linear regression of peak area ratios against standard concentrations. Quality controls were prepared as

described above with concentrations of 25, 150, and 700 ng/mL. The limit of detection was 10 ng/mL. The intraday and interday variability was 10% or less.

Lovastatin or pravastatin. Serum concentrations of lovastatin and pravastatin were determined by a method that used gas chromatography-mass spectrometry, which has been described in detail by Morris et al.26 The lactone of lovastatin was quantitatively converted to the free acid by base hydrolysis, and simvastatin was used as internal standard. A structural analog, SQ- 3 1,900 (Bristol-Myers Squibb, Princeton, NJ), was used as the internal standard for pravastatin. The penta- fluorobenzyl and trimethylsilyl derivatives of the free acids were quantified with use of negative ion chemical ionization (Finnigan SSQ 7000) and the fragment ions at m/z 639 and 565 for pravastatin and lovastatin, respectively, which correspond to the loss of the penta- fluorobenzyl group. The detection limit for both com- pounds was 0.5 ng/mL. All serum concentrations are reported as sodium salt equivalents, not as the free acid.

Data analysis The area under the serum concentration-time curve

(AUC) up to the last measured sample was determined by a combination of log trapezoidal and linear trapezoidal methods.27 The terminal elimination rate constant (k,) was determined by unweighted log-linear regression of the 4 terminal serum concentration-time points. The AUC was extrapolated to infinity with use of the ratio of the terminal serum concentration to k,. Half-life was determined from 0.693/k,. Steady-state diltiazem concentrations were determined from the

372 Azie et al. CLINICAL PHARMA COLOGY & THERAPEUTICS

OCTOBER 1998

= E

?s 0 0 Control Diltiazem

IO:

0 250 500 750 1000 1250 1500

Time (min)

Figure 2. Serum concentration-time profiles for lovastatin in the presence (circles) and absence (squares) of diltiazem (120 mg twice a day for 14 days). Data represent the mean values at each time point for 10 volunteers.

Table II. Pharmacokinetics of lovastatin in the presence or absence of diltiazem

AUC Subject No. (ng/mLJmin)

Control Diltiazem

Glax t nun AUC c mar

t l7wl.r tx (h) (n&L) (min) (ng/mUmin) tx (4 (n&4 (min)

1 7,330 10.8 10 150 12,325 9.6 30 150 2 4,680 10.5 9 150 13,276 10.9 24 150 3 2,966 11 5 150 29,834 13.4 33 150 4 2,827 5.4 5 150 13,274 9.2 29 120 5 3,695 15.2 3 240 8,036 7 15 150 6 2,896 11 3 45 8,061 20.5 14 90 7 2,506 4 4 150 11,730 13.6 16 150 8 2,128 3.8 6 150 15,043 20.5 43 60 9 4,219 27.4 7 120 6,360 10.2 24 150

10 2,826 25.9 6 150 10.918 8.7 32 150

Mean 3,607 13 6 150 12,886* 12 26* 150 SD 1,525 8 2 47 6,558 5 9 32

AUC, Area under the serum concentration-time cutve; tv terminal half-life; C,,,,, maximum serum concentration; &,,, time to reach maximum serum concentration. *Significantly different from control (P < .05).

0- to 12-hour AUC. All data are expressed as mean values + SD and were analyzed by the 2-sided Student t test for paired values at a significance level of P I .05. Stepwise multiple linear regression was performed with the JMP statistical package, with model discrimination using an F-test (SAS Institute, Car-y, NC).

The relationship between area under the serum concentration-time curve of lovastatin in the presence

(AUC’) and absence (AUC) of diltiazem and average diltiazem serum concentration (I) was examined by means of unweighted linear regression with equation l*%

AUC’/AUC = (1 + I/K,) (1)

in which Ki is the equilibrium inhibition constant of the putative inhibitor, diltiazem. This relationship assumes that (1) the inhibition is competitive in nature, (2) the

(:LINICAL PHARMACOLOGY Sr ‘I’HERAPEUl’ICS X’OLUME 64, NUMBER 4 Azie et al. 373

100

F

P 0 0 Control Diltiazem

E 10 10 ‘Z 2

E

8 s 1 1

00 c c .- .- t;i t;i

2 2 0.1 0.1

z z a' a’

0 04 I I I

0 0 100 100 200 200 300 300 400 400 500 500

Time (min) Time (min)

Figure 3. Serum concentration-time profiles for pravastatin in the presence (circles) and absence Figure 3. Serum concentration-time profiles for pravastatin in the presence (circles) and absence (squares) of diltiazem (120 mg twice a day for 14 days). Data represent the mean values at each (squares) of diltiazem (120 mg twice a day for 14 days). Data represent the mean values at each time point for 10 volunteers. time point for 10 volunteers.

Table III. Pharmacokinetics of pravastatin in the presence or absence of diltiazem

Control Diltiazem

AUC C nuu t mclz AUC c mM

t nlM Subject No. (ng/mUmin) tx (h) (n@G (min) (ng/mUmin) tx (4 (ng/mL) (min)

1 2 3 4 5 6 7 8 9

10

48 1.2 136 b 1.8 150 t, 3.0 51 58 %

1.2 1.5

18 i/z 2.7 9 0.9

62 1.6 35 1.2

177 1.7

29 60 48 0.5 27 60 63 60 136 1.0 76 45 70 60 112 1.0 61 60 26 60 122 1 .o 81 45 26 45 35 1.4 14 45 7 90 33 1.1 19 45 4 60 3 0.5 2 150

32 60 65 0.9 32 90 14 45 30 0.7 15 90 64 90 180 1.9 100 60

Mean 74 1.7 33 63 76 1.0 43 69 SD 58 0.7 24 15 58 0.4 34 33

loss of drug during absorption and elimination is solely attributable to hepatic extraction, and (3) hepatic elimination is consistent with the well-stirred model of hepatic clearance. It should be noted that CYP3A substrates, such as lovastatin, may experience significant gut wall elimination, and therefore equation 1 is not strictly valid. For such substrates equation 2 is applicable:

AUC’/AUC = (FG’/FG) (1 + I/K,) (2)

in which F,’ and F, are the intestinal wall availabili- ties in the presence and absence of the inhibitor.

RESULTS Diltiazem administration resulted in a substantial

increase in the AUC of lovastatin, as illustrated by the average serum concentration-time curves shown in Fig- ure 2. The percentage of the total AUC that was extrapolated beyond the last sample was 26% + 11%. The cor-

374 Azie et al. CLINICAL PHARMA COLOGY &THERAPEUTICS

OCTOBER 1998

a

Figure 4. Relationship between the observed and regression model predicted values for the ratio of lovastatin area under the serum concentration-time curve (AUC) in the presence and absence of diltiazem. The broken line represents the 95% confidence interval for the predicted values. A, Relationship when diltiazem steady-state concentration is the independent variable (equation 1). B, Relationship when both diltiazem steady-state concentration and the reciprocal of the control lovastatin AUC are independent variables.

responding pharmacokinetic parameters are listed in Table II. Diltiazem significantly increased the AUC (P < .05) and maximum serum concentration (P < .OS) of lovastatin, without influencing the terminal half-life or time to reach maximum serum concentration. The percentage increase in lovastatin AUC that resulted from diltiazem administration ranged from 51% to 906%. In contrast to lovastatin, the average serum concentration-time curves indicate that diltiazem had no discernible effect on pravastatin pharmacokinetics (Fig- ure 3). This is confirmed by the lack of significant changes in the pharmacokinetic parameters listed in Table III. The percentage of the total AUC that was extrapolated beyond the last sample was less than 5%.

There was no significant difference in steady-state or trough plasma concentrations of diltiazem between the lovastatin and pravastatin treatment groups, and the values decreased within the range expected for the dose and formulation used (Table I).*9 The relative increase in lovastatin AUC was significantly related to the steady-state concentration of diltiazem (Figure 4, A; P = .03; r2 = 0.45) and the corresponding estimate (&SE) of Ki was 70 + 20 nmol/L (29 ng/mL; equation 1). In addition, the relative increase in lovastatin AUC caused by diltiazem plus lovastatin was inversely related to the control period AUC of lovastatin alone (P = .055; r2 = 0.39). A linear combination of diltiazem steady-state concentration and the reciprocal of the control AUC resulted in a significantly improved prediction (P = .002) of the relative increase in lovastatin AUC

(Figure 4, B; 9 = 0.83). Similarly, the product of diltiazem concentration and reciprocal of control lovastatin AUC also resulted in a significant improvement (P = .OOl) in the prediction of relative increase in AUC (r2 = 0.74) compared with inhibitor concentration alone.

DISCUSSION Pravastatin sodium is a hydrophilic HMG-CoA reduc-

tase inhibitor and a tissue-selective cholesterol-lowering agent.10vll In vivo and in vitro studies have suggested that pravastatin is minimally metabolized, and not significantly, by cytochrome P450 (CYP) enzymes in the 3A subfamily.10-l*JO~31 After an oral dose of pravastatin, the predominant drug-related component in urine, feces, and plasma is intact drug. The major metabolite, 3’a- hydroxypravastatin, constitutes about 10% of urinary radioactivity, and at least 15 other metabolites have been detected, none of which contribute more than 6% of the total urinary radioactivity.10,32

In contrast to pravastatin, lovastatin is a la&one pro- drug that requires activation by plasma hydrolases (esterases) to produce an active hydroxy acid (lovastatin acid; Figure 1). Metabolism of lovastatin by rat and human liver microsomes results primarily in the formation of 6’P-hydroxylovastatin, 6’-exomethylenelova- statin, and 3’-hydroxylovastatin, and these oxidations are catalyzed by CYP. 33 Despite similarities in structures, these metabolic steps do not occur to a significant extent with pravastatin, presumably because of different substituents at the 6’ position of the decalon ring

CLINICAL PHARMACOLOGY 8r THERAI’ELWICS VOLUME 64. SI’MBER 4 Azie et al. 375

(Figure 1).6 Antibodies prepared against various cytochrome P45Os have been used to identify CYP3A proteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes.3’ Correlation between lovastatin oxidation and the CYP3A content in human liver microsomes was excellent.“4 The 6’/3-hydroxylation and 3’-hydroxylation of lovastatin by CYP3A4 results in the formation of potent inhibitors of HMG-CoA reductase that account for the majority of lipid-lowering activity.jS,36

The calcium channel antagonist diltiazem is a substrate and an effective inhibitor of CYP3A in vitro or in vivo. 14~39 In humans, concurrent administration of diltiazem with known CYP3A substrates increases the AUC and their pharmacologic effect. Oral midazolam AUC is increased by 200% to 300%40 and that for triazolam by 300%.15 Our study shows that coadministration of 2 well- characterized substrates of CYP3A enzymes-lovastatin and diltiazem-results in a significant increase in the plasma concentration of lovastatin. This is not an unex- pected outcome and is consistent with numerous other clinically important interactions among CYP3A substrates and inhibitors. For example, Neuvonen and JalavaZO showed that itraconazole. another potent inhibitor of CYP3A, increased the plasma concentration of lovastatin in healthy volunteers by IO- to 30-fold. Other seminal examples of such interactions include increased plasma concentrations of terfenadine, cyclosporine, and midazolam in the presence of macrolide antibiotics, “conazole” antifungals, and calcium channel blockers.15,41,42 The general outcome of such interactions is an exaggerated pharmacologic response or toxicity as an expected consequence of enhanced exposure to the drugs alone. With lovastatin, myotoxicity appears to be caused by the parent drug, whereas the lipid-lowering effect is caused by both the parent drug and metabolites. We have therefore provided evidence to suggest that inhibition of CYP3A4 activity by diltiazem in patients receiving lovastatin may adversely affect the risk to benefit ratio. In contrast, this is not the case with pravastatin because it is not metabolized by CYP3A.u

The significant interaction between lovastatin and diltiazem at the dose given cannot be predicted a priori with the traditionally used oral drug-drug interaction model (equation l).Z7 The average steady-state concentration of diltiazem in our study was -0.3 pmol/L. We have determined, as have other studies,14M that diltiazem is a competitive inhibitor of CYP3A in vitro with a Ki value of 50 to 100 pmol/L. Conventional theory would therefore predict no pharmacokinetic interaction at the serum concentration attained because the I/Ki ratio is extremely low (equation 1). A possible explanation for the failure of this

model to accurately predict the observed interaction could be that the effective concentration of inhibitor was under- estimated by at least 200-fold, which may occur with selective partitioning of diltiazem into the liver. Based on our observation that diltiazem did not alter the half-life of lovastatin, we concluded that hepatic and systemic clearance were also unaffected. The “partition coefficient” of at least 200-fold is therefore an unlikely explanation.

An alternative explanation is that there was significant CYP3A-mediated first-pass elimination in the liver and the gut wall, which were exposed to a higher concentration of diltiazem. Moreover, the high concentrations of diltiazem present at the villi of the small intestine and, to a lesser extent, in the portal venous blood during the absorption of lovastatin are consistent with an enhanced bioavailability of lovastatin but not a reduced systemic clearance. The low estimated systemic availability of 5% to 30% for lovastatin suggests that inhibition of first-pass elimination alone would be sufficient to explain the magnitude of the interaction we observed.” This point is emphasized by equation 2, which predicts that complete inhibition of gut wall metabolism alone, for a drug dis- playing a baseline gut wall availability of lo%, would result in a IO-fold increase in the oral AUC. Equation 2 therefore represents the preferred framework for predict- ing drug interactions with CYP3A substrates, but its application is currently limited by the general lack of estimates for gut wall availability. The capability of diltiazem to irreversibly inhibit CYP3A enzymes45 and inhibit p-glycoprotein-mediated transport46,“7 in the gut wall may also contribute to its propensity to elicit drug interactions in vivo.

There was a dramatic increase in lovastatin serum concentrations in some individuals treated with diltiazem, but only a modest effect was observed in others (range, 5 1% to 906%). We identified 2 independent variables that together accounted for almost 85% of the interindividual variation in the magnitude of interaction (Figure 4). The steady-state concentration of diltiazem was independently identified as an important variable; this result would be expected, at least for the reduction in hepatic intrinsic clearance and subsequent increase in hepatic availability. However, high inhibitor concentration results in a profound interaction in a given individual only when that individual has a high level of CYP3A activity as reflected by a low baseline AUC for lovastatin. Individuals with relatively little CYP3A activity and therefore high AUC values at baseline did not experience a large interaction, even at high inhibitor concentrations. This relationship is consistent with the structure of equation 2 if (1) gut wall availability in the presence of inhibitor (FG’) approaches unity and (2) con-

376 A.&e et al.

trol gut wall availability (FG) is proportional to control AUC as a result of a relative invariance in hepatic clearance and extraction ratio. The steady-state diltiazem concentrations and control AUC for lovastatin were not correlated, presumably because non-CYP3A pathways, such as deacetylation, play an important role in diltiazem clearance.4* Individuals that are passively or iatro- genitally induced with respect to CYP3A activity might therefore be expected to have the most dramatic eleva- tions in lovastatin serum concentrations with potent inhibitors of this enzyme subfamily.

This type of drug-drug interaction will most likely extend to other HMG-CoA reductase inhibitors, such as simvastatin, which is also metabolized by CYP3A, and to the numerous other inhibitors of CYP3A. The likeli- hood of this drug interaction is likely to be high, given the prevalent comorbidities of coronary artery disease, hypertension, and hypercholesterolemia. Inhibitors of CYP3A have been shown to worsen the side-effect profile of CYP3A-activated HMG-CoA reductase inhibitors. For example, erythromycin and cyclosporine coadministration with lovastatin and simvastatin increased the incidence of rhabdomyolysis from 5% to 30%, presumably because of elevated parent drug con- centrations2Q@ Analogous interactions may occur when these drugs are given with diltiazem, and future studies should assess whether the interaction we have described decreases efficacy or increases toxicity of other “lovastatin-type” HMG-CoA reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.

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the interaction of diltiazem with lovastatin and pravastatin*

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