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Published: 6 March 2014

Drug Metabolism - The Importance of Cytochrome P450 3A4

Prescriber Update 35(1): 4–6
March 2014

Key Messages

  • CYP3A4 is responsible for the metabolism of more than 50% of medicines.
  • CYP3A4 activity is absent in new-borns but reaches adult levels at around one year of age.
  • The liver and small intestine have the highest CYP3A4 activity.
  • Some important CYP3A4 interactions are due to intestinal rather than hepatic enzyme inhibition (eg, grapefruit).
  • There is considerable variability in CYP3A4 activity in the population.
  • Women have higher CYP3A4 activity than men.
  • Potent inhibitors of CYP3A4 include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit.
  • Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, St. John’s Wort and glucocorticoids.


Cytochrome P450 enzymes are essential for the metabolism of many medicines and endogenous compounds. The CYP3A family is the most abundant subfamily of the CYP isoforms in the liver. There are at least four isoforms: 3A4, 3A5, 3A7 and 3A43 of which 3A4 is the most important1.

CYP3A4 contributes to bile acid detoxification, the termination of action of steroid hormones, and elimination of phytochemicals in food and the majority of medicines2,3.

Data sheets on the Medsafe website (www.medsafe.govt.nz) and the New Zealand formulary (www.nzf.org.nz) are useful sources of information on individual drug-drug interactions.

Age-related Changes and Gender Differences

Foetal levels of CYP3A4 expression, content and activity are very low, but appear to reach adult levels at around one year of age1.

Clinical studies indicate that women metabolise drugs which are substrates of CYP3A4 more quickly than men (20–30% increase)4. Analyses have shown around two fold higher levels of CYP3A4 protein in female compared to male tissue samples3,4

Location

CYP3A4 is mainly located in the liver and small intestine and is the most abundant cytochrome in these organs1. However, CYP3A4 levels in the intestines are not correlated with those of the liver3.

Some medicines which are substrates of CYP3A4 have low oral (but not intravenous) bioavailability due to intestinal metabolism. The bioavailability of these substrates is dramatically changed by inhibition, induction or saturation of CYP3A45.

Polymorphisms

The population variability of CYP3A4 activity is extremely high (>100-fold)3,6.

Some variability can be attributed to allelic variation. A recently discovered single nucleotide polymorphism (CYP3A4*22) appears to be associated with decreased expression and activity (1.7 to 5 fold less). However, the frequency of this variant at around 2% of the population limits its contribution to overall CYP3A4 variability1, 2, 3.

Another identified polymorphism is CYP3A4*1B which occurs at a frequency of 2–9% in some populations. However, a functional effect of this variant has not been established3.

Hepatic and intestinal expression of CYP3A4 exhibits a unimodal distribution of activity suggesting that the population variability is not due to genetic polymorphism of the enzyme itself2.

Nevertheless, there are indications of substantial heritability3. Variation in CYP3A4 among healthy individuals is most likely to be the result of differences in homeostatic regulatory mechanisms2.

Effect of Disease

In disease states, the inherent variability of CYP3A4 mediated drug metabolism is potentially exacerbated by many factors including alterations in hepatic haemodynamics, hepatocellular function, nutrition, circulating hormones, as well as drug-drug interactions2,3.

It has also been increasingly recognised that inflammatory mediators associated with a range of disease states are capable of having profound effects on CYP3A4 gene expression2.

Patients with inflammation, particularly elevated acute phase proteins such as C-reactive protein (CRP) have been noted to have reduced CYP3A4 function2. This is clinically relevant in cancer patients because tumours can be a source of systemically circulating cytokines3.

Acute systemic hypoxia (eg, in chronic respiratory or cardiac insufficiency) appears to up-regulate CYP3A4 activity7.

Reports of CYP3A4 activity in critically ill children showed significantly lower CYP3A4 metabolism1, 8

Inhibition

CYP3A4 is subject to reversible and mechanism-based (irreversible) inhibition. The latter involves the inactivation of the enzyme via the formation of metabolic intermediates that bind irreversibly to the enzyme and then inactivate it6. The clinical effects of a mechanistic inactivator are more prominent after multiple dosing and last longer than those of a reversible inhibitor6.

Medicines that are potent CYP3A4 inhibitors include (but are not limited to) clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, and verapamil9.

Common drug-drug interactions involving CYP3A4 include:

One form of reversible inhibition occurs due to competition between CYP3A4 substrates (eg, oestrogen and antidepressants during the late luteal phase of the menstrual cycle)4.

Induction

CYP3A4 activity is induced via the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), peroxisome proliferator-activated receptor (PPARα) and probably the glucocorticoid receptor (GR)3, 11.

The magnitude of CYP3A4 induction can be substantial. Induction becomes apparent more slowly than inhibition and it takes more time for the induction to stop affecting medicine metabolism. For example, the induction of CYP3A4 by rifampicin takes around six days to develop and 11 days to disappear11.

Induction normally results in a decrease in the effect of the medicine. However, it can lead to increased toxicity if the increased metabolism of the parent compound is accompanied by an increase in exposure to a toxic metabolite11.

Medicines that are potent inducers include phenobarbital, phenytoin and rifampicin9. Many glucocorticoids in clinical use also induce CYP3A4. Some organochlorine pesticides such as dichlorodiphenyltrichloroethane and endrin also induce CYP3A411.

Herb and Food Interactions

Popular dietary supplements and foods that have a high risk for interaction with medicines metabolised by CYP3A4 include (but are not limited to) the following.

Goldenseal

Goldenseal (Hydrastis Canadensis) is often taken to try to prevent common colds and upper respiratory tract infections. It has been reported to reduce CYP3A mediated activity by 88%, equivalent to that seen with clarithromycin12.

Black pepper

Black pepper (Piper nigrum) has been used as a flavouring agent and medicine. When used for flavouring food it is not likely to affect the metabolism of most medicines12. However, excessive use or use in dietary supplements (piperine or piperamides greater than 10 mg) may produce clinically significant interactions, including CYP3A4 inhibition12.

Schisandra

Preparations of fruits from woody vines of Schisandra species are used in traditional Chinese, Japanese and Russian medicine, often as hepatoprotective agents12. Currently available clinical data strongly suggest that Schisandra extracts pose a significant risk for elevating blood levels of medicines that are CYP3A substrates12.

St John’s Wort

This is used for its antidepressant activity. The active substance is hyperforin, the most potent known activator of PXR12. Clinical studies have demonstrated that products containing less than 1% hyperforin are less likely to produce interactions12. However, most products contain 3% hyperforin12.

Grapefruit

Grapefruit (all sources) is a potent inhibitor of intestinal CYP3A4 that has been proposed to interact with more than 44 medicines and result in serious adverse effects13.

Healthcare professionals should ask patients about their use of complementary and alternative medicines when considering the use of a medicine that is altered by CYP3A4.

References

  1. Ince I, Knibbe CA, Danhof M, et al. 2013. Developmental changes in the expression and function of cytochrome P450 3A isoforms: evidence from in vitro and in vivo investigations. Clinical Pharmacokinetics 52: 333–345.
  2. Kacevska M, Robertson GR, Clarke SJ, et al. 2008. Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opinion on Drug Metabolism and Toxicology 4: 137–149.
  3. Zanger UM, Schwab M. 2013. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology and Therapeutics 138: 103–141.
  4. Soldin OP, Chung SH, Mattison DR. 2011. Sex differences in drug disposition. Journal of Biomedicine and Biotechnology 2011: 187103.
  5. Kato M. 2008. Intestinal first-pass metabolism of CYP3A4 substrates. Drug Metabolism Pharmacokinetics 23: 87–94.
  6. Zhou SF. 2008. Potential strategies for minimizing mechanism-based inhibition of cytochrome P450 3A4. Current Pharmaceutical Design 14: 990–1000.
  7. du Souich P, Fradette C. 2011. The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression. Expert Opinion on Drug Metabolism and Toxicology 7: 1083–1100.
  8. de Wildt SN. 2011. Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and children. Expert Opinion on Drug Metabolism and Toxicology 7: 935–948.
  9. Lynch T, Price A. 2007. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. American Family Physician 76: 391–396.
  10. Medsafe. 2011. Statin interactions: reports of serious myopathy. Prescriber Update 32: 13­–14. URL: www.medsafe.govt.nz/profs/PUArticles/StatinInteractionsJune2011.htm (accessed 12 February 2014).
  11. Hukkanen J. 2012. Induction of cytochrome P450 enzymes: a view on human in vivo findings. Expert Review of Clinical Pharmacology 5: 569–585.
  12. Gurley BJ, Fifer EK, Gardner Z. 2012. Pharmacokinetic herb-drug interactions (part 2): drug interactions involving popular botanical dietary supplements and their clinical relevance. Planta Medica 78: 1490–1514.
  13. Bailey DG, Dresser G, Arnold JM. 2013. Grapefruit-medication interactions: forbidden fruit or avoidable consequences? Canadian Medical Association Journal 185: 309–16.
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