HMG-CoA Reductase Inhibitors ("-Statins")  

lovastatin (Mevacor^®)

Lovastatin is a HMG-CoA reductase inhibitor, and cholesterol-lowering drug. Lovastatin was studied for a grapefruit juice (GJ) interaction. Ten healthy subjects  in an open randomized crossover trial drank 200 mL DOUBLE STRENGTH grapefruit juice or water for two days before being given a single 80 mg dose of lovastatin (Note: 2-4 times the usual dosage). Peak concentrations of lovastatin and lovastatin acid (an active metabolite) were increased on average 12-fold for lovastatin, and 4-fold for lovastatin acid. The AUC was increased 15-fold for lovastatin and 5-fold for lovastatin acid. The half-life of lovastatin and lovastatin acid was not affected. The authors advised that co-administration of lovastatin with grapefruit juice be avoided.³⁵

The lovastatin monograph notes that there is a concern that an apparent relationship exists between increased plasma levels of active metabolites of HMG-CoA reductase inhibitors, and myopathy (abnormal condition of muscle). Rhabdomyolysis (literally - breakdown of red muscle) with and without renal failure has been reported in patients receiving erythromycin and lovastatin. The benefits and risks of using lovastatin with erythromycin should be carefully considered. In patients receiving lovastatin without concomitant therapies, the risk of myopathy was approximately 0.1%.³⁴

A 15-fold increase in AUC and a 12-fold increase in peak levels is the largest effect of grapefruit juice reported thus far for any interactions with grapefruit juice. However, we must keep in mind that they did use double strength grapefruit juice (to pronounce the effect of the interaction) and a higher than normal dose of lovastatin.

This paper did state that "the susceptibility of various -statin type drugs to interact with grapefruit juice and other CYP 3A4 inhibitors is different, probably because of the dissimilar role of CYP3A4 in their biotransformation."  CYP3A4 plays an important role in metabolism of lovastatin ,simvastatin, atorvastatin and cerivastatin, but other enzymes are mainly responsible for metabolism of pravastatin and fluvastatin.

A group of researchers from Merck (the manufacturer of Mevacor^® (lovastatin)) Research Labs have responded to the above paper with one of their own - using a self-described common dosage regimen and intake of a common amount of single-strength GJ. Sixteen healthy subjects received either 8 ounces of single-strength GJ or water with breakfast for 3 consecutive days, in a randomized crossover fashion. The subjects then received a single 40mg dose of lovastatin in the evening of the third day.  The AUC and Cmax of all active HMG-CoA reductase inhibitors increased by approximately 40% each in the GJ group.  The AUC and Cmax values for lovastatin approximately doubled in the GJ patients, and lovastatin acid AUC and Cmax increased 1.6 fold.  The authors demonstrate a wide discrepancy from the previous study with GJ and lovastatin, and explain it by the fact that they used a normal dose of lovastatin (40mg daily in the evening) and a normal amount of grapefruit juice (one regular strength glass daily with breakfast). They conclude that daily consumption of a glass of regular-strength GJ has a minimal effect on plasma concentrations of HMG-CoA reductase inhibitors after a 40mg evening dose of lovastatin.⁵³

Of interest in this study, several references are made to personal communications with other researchers saying that although realistic amounts of regular strength grapefruit juice appear to affect only intestinal CYP3A4, excessive amounts, such as used in the initial lovastatin-GJ study, also affect hepatic CYP3A4.  It will be interesting to see if further research bears this out.

simvastatin (Zocor^®)

In a randomized crossover fashion, 10 healthy volunteers received either 200 mL water or DSGJ three times daily for 2 days before receiving a single 60mg dose of simvastatin (Note: 3-6x the usual dosage).  GJ increased the simvastatin AUC by 1513%, and the Cmax was increased 842%.   Simvastatin acid AUC was increased 577% and Cmax increased 555% with GJ.  Time to peak concentration of simvastatin was increased from 1 hour to 2.5 hours.  This dramatic effect on simvastatin blood levels is tempered by the fact that double-strength grapefruit juice was used, and a higher than usual dose of simvastatin was used. The authors recommend that concomitant use of grapefruit juice and simvastatin should be avoided, or the dosage of simvastatin should be greatly reduced. Potential adverse effects include rhabdomyolysis, as detailed above for lovastatin.⁴⁶

The same research group conducted a study with simvastatin to characterize the duration of the GJ induced CYP 3A4. Ten healthy volunteers (9 male, 1 female) received simvastatin 40 mg with either water as a control, and either 0, 1, 3 or 7 days after drinking high-dose GJ (200 mL double-strength GJ) three times daily for 3 days in a non-randomized crossover fashion.  As seen with the previous study, significant increases in simvastatin levels after GJ intake were observed on the day 0 study when compared with water. Simvastatin AUC was increased 1250%, with Cmax increased 1104%. Time to peak concentration (Tmax) was also prolonged from 2 hours to 4 hours (100% increase).  This effect was significantly reduced if 24 hours elapsed between the last GJ intake and simvastatin dosing. At this time, simvastatin AUC was increased 105%, and Cmax was increased 136%.  The authors noted that the effect of even high-dose GJ 24 hours after ingestion is only about 10% of that seen with concurrent GJ and simvastatin intake. AUC and Cmax of simvastatin when taken on day 3 and day 7 after last GJ intake were not significantly elevated compared to control, indicating that the interaction potential of even high amounts of GJ intake dissipates within 3-7 days after last GJ ingestion.⁹⁰

This is useful for characterizing the time course of GJ-drug interactions, and fits with prior expectations that the GJ effect can last up to 3 days after last GJ ingestion. It would be nice to see this study repeated with real-world GJ concentrations and amounts consumed (i.e. a single 250 mL glass of single-strength GJ taken daily x3 days), as with the Merck lovastatin study.

In an apparent response to previously controversial results with simvastatin and GJ interactions, the same research team studied a more "normal" GJ intake along with more "normal" simvastatin dosing.

In a randomized crossover design, 10 healthy male subjects aged 20-24 years received a single 40 mg dose of simvastatin following either 200 mL water or SSGJ daily for 3 days. A two week washout was employed between study periods. The simvastatin dose was given at the same time as the last GJ intake (different from the Merck lovastatin study).

Compared to the water group, GJ intake significantly increased the peak blood concentration (Cmax) of simvastatin by 290%, and the total drug exposure at 24 hours (AUC24) was increased by 256%. Time to peak blood level (Tmax) was prolonged by 100% from 1.5 to 3 hours, and half-life was decreased 26%.

GJ significantly intake increased the peak blood concentration of simvastatin acid (Cmax) by 327% and the total simvastatin acid exposure at 24 hours (AUC24) by 235%. Time to peak simvastatin acid level (Tmax) was unchanged, and half-life of simvastatin acid was decreased by 17%.

A marked interindividual variability was observed. The study does not comment whether any subjects experienced adverse events. The authors concluded that once-daily consumption of a single glass of regular-strength GJ considerably increases plasma concentrations of simvastatin and simvastatin acid. Because of the extent of the interaction, and its unpredictability on an individual level, the concomitant intake of grapefruit juice and simvastatin is not recommended.¹²⁰

A case report exists of onset of simvastatin-associated rhabdomyolysis following grapefruit intake. A 40 year old female was taking simvastatin 80 mg daily for familial hypercholesterolemia. She had been tolerating the medication well, until presenting to the Emergency Room with bilateral lower extremity weakness persisting for a period of 10 days. Onset of muscle pain and weakness was gradual and incremental in nature. At the time of admission, the patient was only able to tolerate a walking distance of less than 20 meters (she reported that she had previously been tolerating aerobic exercise regularly). creatine kinase (CK) level was 12640 U/L, myoglobin 6453 mcg/L and AST 623 U/L and ALT 700 U/L.

Further questioning revealed that 14 days prior to admission (4 days prior to first appearance of symptoms), she had started to routinely consume a single fresh grapefruit once daily at breakfast. Fluid replacement and urinary alkalization prevented progression to renal failure, and the patient had a full recovery of function after 6 days. She was switched to a non-statin cholesterol-lowering medication for ongoing therapy without further sequelae.¹¹⁸

atorvastatin (Lipitor^®)

Atorvastatin, a HMG-CoA reductase inhibitor and cholesterol-lowering drug, was studied for a grapefruit juice interaction.  Twelve healthy volunteers received either 200 mL water or DOUBLE-STRENGTH grapefruit juice three times daily for two days before receiving a single 40 mg dose of atorvastatin with either 200 mL water or grapefruit juice in a randomized crossover fashion.  Subjects took an additional 200 mL water or grapefruit juice three times daily on day 4 and 5 as well.  GJ increased the atorvastatin acid AUC by 2.5 fold.  The peak concentration of atorvastatin acid was not affected, but the time to peak concentration and half-life were significantly increased (200% and 70% respectively).  Atorvastatin has two active metabolites: atorvastatin lactone and 2-hydroxyatorvastatin acid which were also affected by GJ, with the AUC of active and total HMG-CoA reductase inhibitors being increased 1.3 fold and 1.5 fold respectively.   Atorvastatin kinetics were affected to a considerably smaller degree than seen in previous GJ interaction studies with lovastatin and simvastatin. The authors concluded that grapefruit juice, at least in large amounts, should not be used concomitantly with atorvastatin, or the dosage of atorvastatin should be reduced accordingly.⁵²

In a randomized, crossover study, 20 healthy Japanese males, aged 20-33 years, received 10 mg atorvastatin (a lower dose compared to what is commonly used in North America) following either water or 250 mL SSGJ given three times daily for 2 days prior to drug administration, and on the day of drug administration. The washout between study periods was 3 weeks.

The results for atorvastatin (A) and its metabolites were as follows:

	A.Acid	A. lactone	2-H A. acid	2-H A. lactone
AUC	33%	59%	22%	8%
Cmax	20%	25%	67%	31%
Tmax	85%	13%	531%	55%
Half-life	9%	31%	63%	61%

The authors concluded that GJ significantly affects the pharmacokinetics of atorvastatin and its metabolites. The elevations in total drug exposure (AUC) and peak concentrations (Cmax) were less than seen with studies completed by other research groups. The authors ascribed these differences to using 1/4 of the atorvastatin dosage that was used in the other study, along with possible contribution of ethnic factors between Caucasian and Japanese subjects. The authors recommended patients taking atorvastatin should be advised to avoid GJ intake, especially in large quantities.¹¹¹

cerivastatin (Baycol^®)

Although there have been no direct studies between grapefruit juice and cerivastatin, based on the similar metabolism, it may be prudent to avoid taking grapefruit juice with cerivastatin.  The manufacturers monograph for cerivastatin states: "...cerivastatin is metabolized via a dual metabolic pathway utilizing at least 2 cytochrome P450 isoenzymes, CYP2C8 and CYP3A4. If one of the metabolic pathways (e.g., CYP3A4) is blocked, cerivastatin is metabolized, although not completely in some cases, by the alternate metabolic route...drugs or common agents such as grapefruit juice that inhibit this enzyme may represent a potential for drug interactions when combined with cerivastatin. Caution should thus be exercised with concomitant use of...[known CYP3A4 inhibitors] or grapefruit juice." ⁵⁸ Cerivastatin was removed from the worldwide market in August 2001 due to concerns with side effects of rhabdomyolysis.

pravastatin (Pravachol^®)

Pravastatin, a HMG-CoA reductase inhibitor and cholesterol-lowering drug, was studied for a grapefruit juice interaction.   Eleven healthy volunteers received either 200 mL water or DOUBLE-STRENGTH grapefruit juice three times daily for two days before receiving a single 40mg dose of pravastatin with either 200 mL water or grapefruit juice in a randomized crossover fashion.  GJ had no significant effects on the pharmacokinetics of pravastatin, other than the Tmax of active HMG-CoA reductase inhibitors was significantly prolonged from 1 hour to 2 hours.⁵² Pravastatin is a hydrophilic HMG-CoA reductase inhibitor with an oral bioavailability of approximately 20%, and is excreted to a significant extent unchanged in the urine.  CYP3A4 plays only a minor role in the metabolism of pravastatin, which explains why pravastatin is not susceptible to interaction with GJ and other CYP3A4 inhibitors. 

In a randomized, crossover study, 20 healthy Japanese males, aged 20-33 years, received 10 mg pravastatin (a lower dose compared to what is commonly used in North America) following either water or 250 mL SSGJ given three times daily for 2 days prior to drug administration, and on the day of drug administration. The washout between study periods was 3 weeks.

Compared to the water group, the pravastatin group showed no statistically significant changes in total drug availability (AUC, unchanged with GJ), peak concentration (Cmax, 13% decrease with GJ), time to peak concentration (Tmax, increased 17% with GJ) or half-life (unchanged with GJ). 

Total exposure (AUC) of pravastatin lactone (the major metabolite of pravastatin) was increased 29% with grapefruit, and peak level (Cmax) was increased 20%, but this was not statistically significant.The authors concluded that repeated GJ intake does not appear to affect the pharmacokinetics of pravastatin.¹¹¹

fluvastatin (Lescol^®)

Although it has not been studied, it is unlikely that there is a significant interaction between GJ and fluvastatin. The manufacturer's monograph states that "fluvastatin is predominantly metabolized by the hepatic microsomal CYP2C9 subclass of the P450 cytochromes. It is not metabolized to a significant extent by other cytochrome subclasses, including CYP3A4."

However, the monograph also states: "...In addition, since fluvastatin demonstrates a moderate affinity for the CYP 3A4 isoenzyme, drugs or common agents such as grapefruit juice that inhibit this enzyme...may represent a potential, at least in some patients, for drug interactions when combined with fluvastatin." ⁵⁹

rosuvastatin (Crestor^®)

Although it has not been studied, it is unlikely that there is a significant interaction between GJ and rosuvastatin. The manufacturer's monograph states that "The major metabolite is N-desmethyl rosuvastatin, which is formed principally by cytochrome P450 2C9. Approximately 10% of a radiolabeled dose of rosuvastatin is recovered as metabolite."¹²¹