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Grapefruit and Drug Interactions

The Dangers and the Benefits

As demonstrated by previous discussion, drug metabolism through CYP3A4 can be a highly complex process and the resultant metabolites may be active or inactive. Thus, the effective dose that results from a given dose of drug can be affected by CYP3A4 inactivation in the gut. The focus of the rest of this report deals primarily with statins (drugs whose interaction with grapefruit juice may prove to be dangerous), and Saquinavir, an HIV protease inhibitor that might interact favorably with grapefruit juice.

Competitive inhibitors that mimic mevalonate, the substrate of HMG-CoA Reductase are commonly known as statins and are prescribed to 12 million Americans each year. These drugs help to reduce plasma cholesterol concentrations and help prevent the onset of atherosclerosis. While there are many types of statins, the chemical structures of Simvastatin (Zocor®), Lovastatin (Mevacor®) and Pravastatin (Pravachol®) are all very similar. The structure of Atorvastatin (Lipitor®) is somewhat different. Each of these structures is shown in Figure 23:

As shown in Table 3, each of the statins, with the exception of Pravastatin, is primarily metabolized (either to a still active or inactive metabolite) by CYP3A4, with very little drug being excreted by the kidneys.

Table 3: Major metabolic pathways for the statins such as CYP3A4 (Martin et al, 2003)

Many studies have been conducted to assess the potential risks involved with grapefruit juice consumption while taking prescribed doses of these statins. What is known about specific interactions between the juice, the statins and the level of danger are discussed next.

Both Simvastatin and Lovastatin are rapidly metabolized by CYP3A4 in the intestines during absorption through the gut. Metabolization by CYP3A4 yields inactive metabolites of each of these drugs. These inactive metabolites are quickly processed and broken down by the body. Thus, consumption of grapefruit juice and the concomitant loss of CYP3A4 activity in the intestines results in greater bioavailability and serum concentrations of the active, unmetabolized drug. The following data analyses reveal the dangers of combining grapefruit juice and either simvastatin or lovastatin.

Figure 24: Simvastatin and Simavastatin acid levels in serum after different doses and ingestions of grapefruit juice (Lilja et al, 2000)

Figure 24 measures the plasma concentration of Simvastatin in treated patients over time following a 40mg dose of Simvastatin. The line indicated by the closed triangles represents those patients that consumed grapefruit juice and the drug together. The measure of bioavailability used most commonly by researchers is to measure the difference in the area under the curve (AUC) of each of the time-dependent graphs. For Simvastatin there was a 16-fold increase in bioavailability and a 7-fold increase in the bioavailability of Simastatin acid as compared to the water control group (open circles). Furthermore, this study indicates that the effects of grapefruit juice can extend for hours or even days. Increased AUC can clearly be seen even 24 hours after consuming grapefruit juice (closed diamonds).

The results of this experiment shows the mean serum concentrations of simvastatin (upper graph) and simvastatin acid (lower graph) in 10 healthy volunteers after single oral doses of 40 mg simvastatin. Simvastatin was taken with 200 mL water, with 200 mL double-strength grapefruit juice after ingestion of 200 mL grapefruit juice three times daily for 2 days, or with 200 mL water 24 hours, 3 days, or 7 days after last dose of grapefruit juice. The top line shows that the maximum bioavailability of simvastatin and simvastatin acid is achieved with the maximum dosage of 200mL double-strength grapefruit juice (Lilja et al, 2000).

Figure 25: Lovastatin and Lovastatin acid levels in serum after oral ingestion with water or grapefruit juice (Dahan et al, 2003)

Figure 25 shows the serum concentrations of lovastatin and lovastatin acid after a single oral dose of 80 mg lovastatin. The levels of both lovastatin and its metabolite lovastatin acid are increased in blood serum after ingestion with grapefruit juice versus ingestion with water.

Results for Lovastatin and Lovastatin acid were similar, showing a 15-fold and a 5-fold increase in the AUC respectively. These results can clearly be seen in Figure 25 where the closed circles represent the group that consumed grapefruit juice with the drug.

Because of these findings, patients taking either lovastatin or simvastatin should avoid drinking grapefruit juice at any time. Due to the increased bioavailability caused by CYP3A4 inactivation, patients combining grapefruit juice with either of these two drugs would receive doses which are far higher than the limits tested during clinical trials.

Unlike Simvastatin and Lovastatin, when Atorvastatin is processed by CYP3A4, the metabolites remain active and, in fact, account for 70% of the effect of the drug. Given this fact, the exact effects of CYP3A4 inhibition on Atorvastatin are somewhat hard to predict. Studies conducted in Finnish and Japanese populations found that, in general, consuming grapefruit juice with Atorvastatin can increase bioavailability, but not to the same degree as seen in experiments with Simvastatin and Lovastatin (Lilja et al, 2000). The Finnish study monitored the effects of grapefruit juice consumption on serum concentrations of Atorvastatin and its primary metabolite 2-hydroxyatorvastatin. The details are show in Figure 26:

Figure 26: Levels of Atorvastatin and its primary metabolite in patients who consumed water versus grapefruit juice (Lilja et al, 2000)

Figure 26 shows serum concentrations of atorvastatin acid and lactone (upper panel) and 2-hydroxyatorvastatin acid and lactone (lower panel) in 12 healthy volunteers after a single dose of 40 mg atorvastatin, after ingestion of 200 mL double-strength grapefruit juice (solid circles) or water (open circles) three times a day for 2 days, and on day 3 with atorvastatin and ½ hour and 1 ½ hours after atorvastatin administration. In addition, 200 mL grapefruit juice or water was ingested three times a day on days 4 and 5.

As can be seen from these graphs, grapefruit juice consumption causes an increase in the bioavailability (again measured as the area under the curve) for both Atorvatstatin acid and Atorvastatin lactone. However, because CYP3A4 is inactivated by the grapefruit juice consuming group, the patients' serum levels of the primary active metabolite are much lower. When these two facts are combined, the overall effects tend to cancel each other out as can be seen in Figure 27:

Figure 27: Graphs showing the bioavailiability of both total and active Atorvastatin in the blood after consuming grapefruit juice (dark circles) (Lilja et al, 2000)

Figure 27 shows serum concentrations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in 12 healthy volunteers after a single dose of 40 mg atorvastatin, after ingestion of 200 mL double-strength grapefruit juice (solid circles) or water (open circles) three times a day for 2 days, and on day 3 with atorvastatin and ½ hour and 1 ½ hours after atorvastatin administration. In addition, 200 mL grapefruit juice was ingested three times a day on days 4 and 5.

These results show that combining Atorvastatin and grapefruit juice only results in a 2.5-fold increase in overall Atorvastatin bioavailability. Since such an increase falls within dosing norms for this drug, the effects of grapefruit juice consumption would not be as dangerous as combining juice with Simvastatin and Lovastatin in most people. However, individuals sensitive to higher doses may still be affected and caution should be exercised in combining grapefruit juice with Atorvastatin.

Out of all of the statins discussed thus far, Pravastatin is the only one not directly metabolized by CYP3A4. Though its chemical structure is remarkably similar to that of Simvastatin and Lovastatin, its chemical properties are quite unique. As seen in Figure 28, grapefruit juice consumption has little affect on the bioavailability of Pravastatin.

Figure 28: Pravastatin levels in serum with water (white) or grapefruit juice consumption (black) (Lilja et al., 2000)

Figure 28 shows that serum concentrations of Pravastatin in 11 healthy volunteers after a single dose of 40 mg pravastatin, with ingestion of 200 mL double-strength grapefruit juice or water three times a day are highly similar. Thus, it appears that Pravastatin levels are unaffected by the consumption of grapefruit juice.

Given these data, Pravastatin might be an effective alternative for those who require statin medication but enjoy drinking grapefruit juice.

While most statins react unfavorably with grapefruit juice, increasing serum concentrations of the drugs to dangerous levels, combining grapefruit juice to enhance the bioavailability of certain drugs might actually be beneficial. Saquinavir is an inhibitor of HIV protease and is commonly used in conjunction with reverse transcriptase inhibitors in the treatment of HIV and AIDS. Unfortunately, this drug is highly metabolized by CYP3A4 and as such its bioavailability is generally between 1-4%. Saquinavir is also very expensive to manufacture and so anything that could reduce the necessary dose (usually 600-800mg) would greatly reduce costs for those with HIV. In a study which combined grapefruit juice and oral Saquinavir, it was found that drinking grapefruit juice along with Saquinavir doubled its bioavailability. An additional study, (Figure 29), analyzed the affect of a known inhibitor of CYP3A4 on Saquinavir transport across an epithelial monolayer (Eagling et al, 1999).

Figure 29: The cumulative transport of Saquinavir across intestinal cell monolayers under certain CYP3A4 inhibitory drug conditions (Eagling et al, 1999)

In Figure 29, a represents the transport of Saquinavir alone. The black line represents transport from the apical to basal lateral side while the white line represents drug transport from the basal lateral to apical side. Both b and c represent transport of Saquinavir in the presence of CYP3A4 inhibitors.

These results in Figure 29 show that reverse transport across the cell (representative of transporting a drug out of the blood and back into the gut lumen) is greatly inhibited by verapamil and ketoconazole, both inhibitors of CYP3A4. Grapefruit juice was expected to produce results similar to those seen in these graphs. Not only does inactivating CYP3A4 prevent retrograde transport of Saquinavir, it also increases the rate at which the drug is pumped into the bloodstream. These findings corroborate other studies that indicate the potential benefit of increased bioavailability derived from combining grapefruit juice and Saquinavir in the treatment of AIDS.