Correspondence

To the Editor: I appreciate reading a review of this issue that is both thorough and concise. But I have a few questions:

1. What is the source for Figure 3? What is the basis or definition for designating a particular CYP as the primary pathway? Is this based on in vitro or in vivo data?

2. Considering the role of CYP 2C19 genotype in metabolism of PPIs, is it really possible to specify the primary pathway of metabolism without accounting for differences between extensive and poor metabolizers of CYP 2C19?

3. Other then the observations that PPIs have short serum half-lives and competitively inhibit CYP 2C19, I have not seen other data that supports the idea of separating PPI doses from other drugs to avoid a CYP 2C19-mediated interaction. Two references are given (20, 21), but only 20 (Li et al study) is listed in the bibliography.

Thanks,
Jill Allen, PharmD, BCPS

References:

1. McNally PR. Clopidogrel and PPI Competition for CYP2C19: "Heart Attack or Heartburn?” http://www.vhjoe.org/Volume8Issue2/8-2-7.htm

Author's Response:

The author appreciates Dr. Allen’s thoughtful review of the manuscript, “Clopidogrel and PPI Competition for CYP2C19: "Heart Attack or Heartburn?”1 and an itemized response appears below.

1. The summary data used to develop Figure 3 appearing in this article was derived from a variety of sources on the hepatic metabolism of the proton pump inhibitor (PPIs) drugs.^2,3,4,5,6 The designation of “primary” versus “secondary” CYP metabolic pathway is an old term; derived from semi-quantitative estimates determined from both in vitro and in vivo human experiments.^7,8 In vitro, human liver microsome experiments by Li, et al,² examined the inhibitory effects of the proton pump inhibitors on a family of P450 enzymes (CYP2C9, 2C19, 2D6 and 3A4). Perhaps a more useful way to demonstrate the degree of PPI CYP-subgroup metabolism is to express metabolism in relative kinetic terms lowest (1=unity) to highest (x multiples), as shown in Table 1.

Table 1. K_i values listed in relative proportional values of inhibition of CYP human liver microsomes by individual proton pump inhibitors. Lowest Ki inhibition expressed as unity (1). For CYP2D6, the concentration of PPIs that caused 50% inhibition of the marker reaction (IC₅₀) was determined at a substrate close to K_m. Data shown in Table 1 adapted from Li, et al.²

Although Li’s study² provides the most comprehensive in vitro evaluation for PPIs interaction with human hepatic microsomes, the complexity of “in vitro” drug and P450 interactions prohibit direct extrapolation to clinical practice. For example, lansoprazole is predominantly metabolized through the CYP3A4 pathway and its “secondary” metabolism through the CYP2C19 “may” have little or no impact on the activation of clopidogrel through the 2C19 pathway. However, consumption of grapefruit juice (a potent 3A4 inhibitor), may shunt lansoprazole metabolism through the 2C19 pathway, thereby competitively inhibiting clopidogrel activation. Likewise the alternative medicine, St John’s wort, is a potent inducer of both CY3A4 and 2C19 pathways and simultaneous administration this with clopidogrel and any of the PPIs may lead to significant drug interactions, Figure 1.

Wilkinson GR. N Engl J Med. 2005;352:2211-21
Mega JL, et al. N Engl J Med. 2009;354-62

The potential for a myriad of CYP interactions between drugs, alternative medicines, and over the counter agents has been carefully reviewed elsewhere^{9,10,11,12,13} and it is summarized in Tables 2 & 3.

Table 2. List of common drugs metabolized through the CYP3A4 microsomal system, and agents that can inhibit or induce the 3A4 microsomal system.

Table 3: List of common drugs metabolized through the CYP2C19 microsomal system, and agents that can inhibit or induce the 2C19 microsomal system.

2. I concur with Dr Allen’s suggestion that genetic polymorphisms for the CYP2C19 pathway make it difficult to specify the “primary” CYP pathway for proton pump inhibitors metabolism and the degree competitive inhibition of the CYP hepatic activation of clopidogrel. The interethnic variability of CYP2C19 pathway is significant,^14,15 with the percentage of CYP2C19 “poor metabolizers” estimated to occur with the following ethnic frequencies: Caucasian 2.8%, African-Americans 3.9%, Chinese 14.3%, Koreans 14% and Japanese 21%.¹⁶

In the same issue of VHJOE, the Literature Review Section, we examined the importance of measuring the Platelet Reactivity Index (PRI) as a biomarker of clopidogrel efficacy.^17,18 Due to the wide ethnic variance in CYP and potential for medicinal and over the counter medication to influence CYP drug disposition and metabolism, future pharmaceutical development may require CYP450 fingerprints be incorporated into study design and data analysis or that biomarkers of drug effect, i.e., PRI and clopidogrel be used.

3. I am unaware of detailed studies examining the effect of spacing the dose administration of PPIs and other drugs that may have CYP interactions. My suggestion that spacing the dose administration of PPI and other drugs is based on the detailed pharmacokinetic data presented in this manuscript.¹ However, as cited in the manuscript,¹ the concept of spacing the administration of PPIs with other drugs requires careful study and confirmation of benefit before such practice can be recommended. The reviewer is correct there were 21 citations in the manuscript and the 21st reference in the bibliography (Meyer UA. Interaction of proton pump inhibitors with cytochrome P450: Consequences of drug interactions. Yale Journal of Biology and Medicine. 1996;69:203-209) was inadvertently excluded and an errata will be submitted to the Editor of VHJOE.

Peter R. McNally, DO, FACP, FACP
University Colorado Denver School of Medicine
Center for Human Simulation
Aurora, Colorado 80045

References:

1. McNally PR. Clopidogrel and PPI Competition for CYP2C19: "Heart Attack or Heartburn?” http://www.vhjoe.org/Volume8Issue2/8-2-7.htm

2. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump inhibiting drugs omperazole, esomprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metabolism and Disposition. 2004;32:821-827. <PubMed>

3. Meyer UA. Interaction of proton pump inhibitors with cytochrome P450: Consequences of drug interactions. Yale Journal of Boliogy and Medicine. 1996;69:203-209. <PubMed>

4. Abelo A, Anderson TB, Antonsson M, Naudot, et al. Stereoselective metabolism of omperazole by human cytochrome P450 enzymes. Drug Metab Dispos. 2000;28:966-72. <PubMed>

5. Chong E and Ensom M. Pharmacogenetics of proton pump inhibitors: a systematic review. Pharmacotherapy. 2003;23:460-471. <PubMed>

6. Gugler R, Hartmann M, Rudi J, Brod I, et al. Lack of pharmacokinetic interaction of pantoprazole with diazepam in man. Br J Clin Pharmacol. 1996;42:249-252. <PubMed>

7. Sach S. The clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther. 2006;23:Suppl 2:2-8. <PubMed>

8. Tucker G. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther. 1994;8:33-38. <PubMed>

9. Wilkinson GR. Drug Metabolism and variability among patients in drug response. N Engl J Med. 2005;352:2211-21. <PubMed>

10. Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Crit Care Clin 2006;22:329-345. <PubMed>

11. Foster BC, Foster MS, Vanderhoek J, Krantis A, et al. An In vitro evaluation of human cytochrome p450 3A4 and P-glycoprotein inhibition by garlic. J Pharmaceut Sci. 2001;4;176-184. <PubMed>

12. Mills E, Wu P, Johnston BC, et al. Natural health product-drug interactions: a systematic review of clinical trials. Ther Drug Monit. 2005;27:549-57. <PubMed>

13. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: A systematic review. Drugs. 2001;61:2163-2175. <PubMed>

14. Kupfer A, Preisig R. Pharmacogenetics of mephemytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol. 1984;26:753-9. <PubMed>

15. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes p450 (CYP) 2D6 and 2C19. Clin Pharmacokinet. 1995;29:192-209. <PubMed>

16. Wedlund PJ. The CYP2C19 enzyme polymorphism. Pharmacology. 2000;61:174-83. <PubMed>

17. McNally PR. Literature Review: Literature Review: FDA: Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix) http://www.vhjoe.org/Volume8Issue2/8-2-8.htm

18. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256-60. <PubMed>

Erratum

To the Editor,

Please note the manuscript, Clopidogrel and PPI Competition for CYP2C19: "Heart Attack or Heartburn?” was published with an inadvertent omission of the 21st reference in the bibliography.

Bibliography

21. Meyer UA. Interaction of proton pump inhibitors with cytochrome P450: Consequences of drug interactions. Yale Journal of Biology and Medicine. 1996;69:203-209. <PubMed>

Would you please consider publishing an Errata in the next issue of VHJOE, to correct this omission.

Respectfully,
Peter R. McNally, DO, FACP, FACP
University Colorado Denver
School of Medicine
Center for Human Simulation
Aurora, Colorado 80045

1. McNally PR. Clopidogrel and PPI Competition for CYP2C19: "Heart Attack or Heartburn?” http://www.vhjoe.org/Volume8Issue2/8-2-7.htm.