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How does cyclosporine increase in pravastatin levels by 5-12 fold?

Summary:

  • Cyclosporine is used by patients who have undergone organ transplantation; as many as 80% of heart transplant and 60% of renal transplant patients will develop post-transplant hyperlipidemia that may require the use of lipid lowering therapy such as pravastatin.
  • Pravastatin primarily undergoes liver phase II metabolism (or non-CYP450 mediated pathways such as conjugation) and is a known substrate of the influx membrane transporters (OATP1B1 and OATP2) and efflux transporters (MRP2 and P-gp).
  • Cyclosporine is a potent inhibitor of several membrane transporters used by pravastatin for transport into and out of various cells including: OATP1B1, OATP1B3, OATP2B1, MRP2, and MDR1 (i.e., P-glycoprotein (P-gp)).
  • Therefore, coadministration of cyclosporine and pravastatin can result in a 5-12 fold increase in plasma pravastatin concentrations as a result of cyclosporine inhibiting influx and efflux transporters involved in pravastatin's overall bioavailability.

Editor-in-Chief:
Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: March 2016

Explanation

  • The 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  

    How does cyclosporine increase the levels of pravastatin if it does not go through the CYP450 enzyme system?
    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. 

    Where does cyclosporine influence this process?

    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.

    References:

    1. Bilchick KC, Henrikson CA, Skojec D et al.  Treatment of hyperlipidemia in cardiac transplant recipients.  Am Heart J  2004;148:200-10.
    2. Ojo AO.  Cardiovascualr complications after renal transplantation and their prevention.  Transplantation  2006;82:603-11.
    3. Kasiske 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.
    4. Cyclosporine (Gengraf) product package insert.  Abbott Laboratories.  Abbott Park, Ill.  June 2004.
    5. Cyclosporine (Neoral) product package insert.  Novartis Pharmaceuticals Corp.  East Hanover, NJ.  August 2005.
    6. Pravastatin (Pravachol) product package insert.  Bristol-Myers Squibb Co. Princeton, NJ.  August 2005.
    7. Neuvonen PJ, Niemi M, Backman JT.  Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.  Clin Pharmacol Ther  2006;80:565-81.
    8. Regazzi 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.
    9. Hedman 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.
    10. Park JW, Siekmeier R, Merz M et al.  Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A.  In J Clin Pharmacol Ther  2002;40:439-50.
    11. Cohen DE, Anania FA, Chalasani N.  As assessment of statin safety by hepatologists.  Am J Cardiol  2006;97:77C-81C.
    12. Thompson PD, Clarkson PM, Rosenson RS.  As assessment of statin safety by muscle experts.  Am J Cardiol  2006;97:69C-76C.
    13. Omar MA, Wilson JP.  FDA adverse event reports on statin-associated rhabdomyolysis.  Ann Pharmacother  2002;36:288-95.
    14. Aryton A, Morgan P.  Role of transport proteins in drug absorption, distribution and excretion.  Xenobiotica  2001;31:469-97.
    15. Shitara 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.
    16. Matsushima 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.
    17. Yamazaki 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.
    18. Rao 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.
    19. Shitara 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.
    20. Hirano M, Maeda K, Shitara Y et al.  Drug-drug interactions between pitavastatin and various drugs via OATP1B1.  Drug Metab Dispos  2006;34:1229-36.

MESH Terms & Keywords

  • cyclosporine, Neoral, Sandimmune, Geograf, pravastatin, pravachol, immunosuppressive drugs, statins, CYP450, P450, organ transplantation, transplant, dyslipidemia, heart transplant, renal transplant, lipid