PAS6012 MEDICAL STATISTICS

PROJECT 1

8 December 2009

060130516

GRAPEFRUIT INTERACTS WITH STATINS

Statins are an important class of cholesterol lowering medications which inhibit enzyme
HMG-CoA reductase, cholesterol producer in the liver. Although generally safe, increased
levels of these drugs in blood increase the risk of dose related side effects, including
muscle inflammation and liver damage.

It has been found that grapefruit interacts with some statins and elevates the area under
the plasma concentration – time curve (AUC), a measure of body’s exposure to the
drug, with no significant change in their systemic clearance.

Statins undergo metabolism through CYP3A4, a predominant enzyme in the small

intestine, to various degrees. Grapefruit inactivates this enzyme in the small intestine
resulting in a significant reduction of drug metabolism. An additional mechanism is
possibly the inhibition of P-glycoprotein, an enzyme which flushes drugs out of the gut
and limits its absorption. These result in the elevation of drug concentration in blood
and higher risk of its side effects. []

But not all the statins interact with grapefruit to the same level. Atorvastatin, lovastatin
and simvastatin are mainly metabolized by CYP3A4 and reports state that grapefruit
juice increases their blood concentration.

Studies have found that consumption of “high-does” grapefruit juice (200ml double-
strength juice 3 times a day prior and after taking medication) increases the AUC of
lovastatin and atrovastatin by 15 and 3 fold respectively[]. However one glass of
grapefruit juice has minimal effect on lovastatin if they are taken with 12 hours interval.
[Error: Reference source not found]

A randomized cross-over trial found that after drinking 200 ml of grapefruit juice per
day for 2 days prior to taking simvastatin and then together with the medication on day
3, the AUC of simvastatin increases by 3.6 fold ( p-value < 0.01) with no significant
change in drug’s clearance. So even one daily consumption of grapefruit juice
considerably increases plasma concentrations of simvastatin.

However it was shown that when simvastatin is taken 24h after ingestion of even “high-
does” of grapefruit juice, the effect on the concentration of simvastatin is only about
10% of the effect observed during concomitant consumption. The effects on CYP3A4
disappear within 3 to 7 days after ingestion of the last dose of juice.[] This suggests that
an interval of 24 hours before medication might prevent a clinically relevant interaction.
[,]
 Notice that the above results were obtained through trials on healthy subjects. They do
not report clinical significance and no exact side effects were reported. The exact extent
of interaction is not predictable for individual patients due to different level of
CYP3A4 in different individual.[Error: Reference source not found] A glass of 250 ml grapefruit
juice can inhibit CYP3A4 for three days.[,]

For pravastatin, fluvastatin and rosuvastatin the interaction is not

clinically significant because they are not substantially metabolised
by CYP34A.[,]

REFERENCES
1. Grapefruit interaction: Not all statins are equal
Jennifer Ng. Canadian Pharmacists Journal DOI: 10.3821/1913-701X-141.sp2.S8

2. Medicinal importance of grapefruit juice and its interaction with various drugs
Jawad Kiani, Sardar Imam. Nutrition Journal 2007, 6:33 doi: 10.1186/1475-
2891-6-33

Word count: 488

APPENDIX

Key words used in the search

Words “grapefruit statin” were entered in PubMed and Google Scholar.

Further Details of References

In Google Scholar “grapefruit statin”.

First article was found on the fifth (at the time of search) page.

Grapefruit interaction: Not all statins are equal

Jennifer Ng, Canadian Pharmacists Journal DOI: 10.3821/1913-701X-141.sp2.S8
http://www.cpjournal.ca/perlserv/?request=get-document&doi=10.3821%2F1913-701X-
141.sp2.S8

In PubMed enter “grapefruit statin”.

Second article is on the first (at the time of searching) page.

Medicinal importance of grapefruit juice and its interaction with various drugs
Jawad Kiani, Sardar Imam. Nutrition Journal 2007, 6:33 doi:10.1186/1475-2891-6-33
http://ukpmc.ac.uk/articlerender.cgi?tool=pubmed&pubmedid=17971226