prescribing of immunosuppressive drugs (in particular cyclosporine) for
patients who have undergone organ transplantation is common and has led to
improvements in rejection-related mortality. However, as many as 80% of
heart transplant and 60% of renal transplant patients will develop
post-transplant dyslipidemia that is, in part, mediated by cyclosporine.1-5
Since immunosuppressive agents typically cannot be stopped or changed, patients
will need lipid-lowering treatment with mortality reducing drugs like HMG CoA
reductase inhibitors (i.e., statins).2 One statin with a profile that is
perceived to be free of drug-drug interactions is pravastatin
(Pravachol). This perception has developed as a result of pravastatin not
being a substrate for any of the commonly known CYP450 isoenzymes found in the
gastrointestinal tract and liver.6,7 In fact, pravastatin primarily
undergoes liver phase II metabolism (or non-CYP450 mediated pathways, such as
conjugation), which results in its elimination by the kidneys (47% of
clearance) and through the bile (53% of clearance).6 However, the
coadministration of cyclosporine and pravastatin can still result in a 5-12
fold increase in plasma pravastatin concentrations.8-10 This is
clinically relevant since increased levels of any statin are known to increase
the risk of both hepatotoxicity and rhabdomyolysis.11-13
does cyclosporine increase the levels of pravastatin if it does not go through
the CYP450 enzyme system?Where
does cyclosporine influence this process
It is first important to understand the basic process of
pravastatin absorption and elimination from the body. After oral
administration, pravastatin will be absorbed in the GI tract primarily by
influx transporters, due to its high degree of hydrophilicity and
decreased ability to penetrate the lipid content of the cell membrane.
These influx transporters are called the organic anion transporting polypeptide
(OATP) 1B1 and OATP2 (this will be very important later).14 This process
of absorption means that pravastatin is a known substrate for OATP1B1 and
OATP2.7,15,16 Once it is inside the enterocytes of the intestinal lumen
it can then easily be kicked back out into the GI tract via two well known
efflux pumps called multidrug resistance protein 1 (MDR1, also known as
P-glycoprotein (P-gp)) and multidrug resistance protein 2 (MRP2).7,9 This
means that pravastatin is also a substrate for P-gp and MRP2 (also important
later). This efflux mechanism out of the enterocytes partially explains
pravastatin's low bioavailability (absorption) of 17% and removal in the feces
by as much as 70%.6 Anything that would inhibit these efflux
mechanisms would increase the overall absorption of pravastatin into the
body. If the pravastatin inside the enterocytes is not transported into
the lumen of the GI tract, it can then be absorbed into the blood for delivery
into the liver via the hepatic portal blood supply. As it enters the
liver, pravastatin's hepatic uptake into the hepatocyte is high (extraction
ratio of 0.66) and most likely occurs via the influx transporters OATP1B1 and
OATP2.6,9,17-19 Once inside the hepatocyte, pravastatin will not only
exert its effects on cholesterol production, but it will also undergo phase II
metabolism in preparation for elimination by the kidneys or for excretion into
the bile via the efflux transporters, P-gp, MRP2, and/or breast cancer
resistance protein (BCRP).7,9,20 Thus, anything that affects either
hepatic influx or efflux transporters will also have an effect on the
pravastatin concentrations seen in the body.
Cyclosporine is a potent inhibitor of several membrane transporters used by
pravastatin for transport into and out of various cells, which include OATP1B1,
OATP1B3, OATP2B1, MRP2, and MDR1 (i.e., P-glycoprotein (P-gp)).4,5,7,9,18
As mentioned before, pravastatin concentrations will not be affected by
cyclosporine's inhibition of CYP450 3A4 because it is not a substrate of any of
the CYP450 enzymes.4-7 Drug interaction studies have shown that
pravastatin concentrations in the body are increased 5-12 fold when given with
cyclosporine.8-10 While some data suggest that the half-life does not
increase proportionally to these concentrations, it is difficult to interpret
the accuracy of such data given these were single dose studies.9
Therefore, due to pravastatin's profile for use of both influx and efflux
transporters and cyclosporine's ability to inhibit many of those same
transporters, the significant increase in pravastatin concentrations is likely
multifactorial. This means that cyclosporine decreases the efflux of
pravastatin back into the GI lumen via its inhibition of the intestinal efflux
pumps (MRP2 and P-gp) located on the apical (luminal) surfaces of the
enterocyte.9 This results in a greater amount of pravastatin entering
into circulation. In addition, pravastatin is not undergoing as much
hepatic uptake, or elimination, because of cyclosporine's inhibition of hepatic
influx and efflux transporters used by pravastatin.9 Therefore,
cyclosporine significantly increases pravastatin concentrations at several
locations in the body.
- Bilchick KC, Henrikson CA, Skojec D et al. Treatment of
hyperlipidemia in cardiac transplant recipients. Am Heart J
- Ojo AO. Cardiovascualr complications after renal transplantation and their prevention. Transplantation 2006;82:603-11.
B, Cosio FG, Beto J et al. Clinical practice guidelines for managing
dyslipidemias in kidney transplant patients: a report from the Managing
Dyslipidemias in Chronic Kidney Disease Work Group of the National
Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J
Transplant 2004;4(Suppl 7):13-53.
- Cyclosporine (Gengraf) product package insert. Abbott Laboratories. Abbott Park, Ill. June 2004.
- Cyclosporine (Neoral) product package insert. Novartis Pharmaceuticals Corp. East Hanover, NJ. August 2005.
- Pravastatin (Pravachol) product package insert. Bristol-Myers Squibb Co. Princeton, NJ. August 2005.
PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs:
mechanisms and clinical relevance. Clin Pharmacol Ther
MB, Iacona I, Campana C et al. Altered disposition of pravastatin
following concomitant drug therapy with cyclosporine A in transplant
recipients. Transplant Proc 1993;25:2732-4.
M, Neuvonen PJ, Neuvonen M et al. Pharmacokinetics and
pharmacodynamics of pravastatin in pediatric and adolescent cardiac
transplant recipients on a regimen of triple immunosuppression. Clin
Pharmacol Ther 2004;75:101-9.
JW, Siekmeier R, Merz M et al. Pharmacokinetics of pravastatin in
heart-transplant patients taking cyclosporin A. In J Clin Pharmacol
- Cohen DE, Anania FA, Chalasani N. As assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C-81C.
- Thompson PD, Clarkson PM, Rosenson RS. As assessment of statin safety by muscle experts. Am J Cardiol 2006;97:69C-76C.
- Omar MA, Wilson JP. FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 2002;36:288-95.
- Aryton A, Morgan P. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica 2001;31:469-97.
Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors:
drug-drug interactions and interindividual differences in transporter
and metabolic enzyme functions. Pharmacol Ther 2006;112:71-105.
S, Maeda K, Kondo C et al. Identification of the hepatic efflux
transporters of organic anions using double-transfected Madin-Darby
canine kidney II cells expressing human organic anion-transporting
polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2,
OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance
protein. J Pharmacol Exp Ther 2005;314:1059-67.
M, Akiyama S, Nishigaki R et al. Uptake is the rate-limiting step in
the overall hepatic elimination of pravastatin at steady-state in rats.
Pharm Res 1996;13:1559-64.
US, Scarborough GA. Direct demonstration of high affinity interactions
of immunosuppressant drugs with the drug binding site of the human
P-glycoprotein. Mol Pharmacol 1994;45:773-6.
Y, Itoh T, Sato H et al. Inhibition of transporter-mediated hepatic
uptake as a mechanism for drug-drug interaction between cerivastatin and
cyclosporin A. J Pharmacol Exp Ther 2003;304:610-6.
M, Maeda K, Shitara Y et al. Drug-drug interactions between
pitavastatin and various drugs via OATP1B1. Drug Metab Dispos