Cytochrome P450 Enzymes

Metabolism by cytochrome P450 enzymes (CYP) is a critical means of drug metabolism, with the liver being the main site of metabolism, although some drugs are metabolised at the site of absorption.1-3 CYP is oforms are able to simultaneously catalyse many metabolic reactions and more than one CYP isoform may metabolise a given substrate.3 However, metabolism of kinase inhibitors is predominantly by CYP3A4 as shown in the table below.1,4

Cytochrome P450 Enzymes Involved in the Metabolism of Select Kinase Inhibitors[5, 6]

Kinase Inhibitor

Major Cytochrome P450 enzymesa

Minor Cytochrome P450 enzymesb

Afatinib

Not an inhibitor/ inducer of P450 enzymes

Not an inhibitor/ inducer of P450 enzymes

Axitinib

CYP3A4, CYP3A5

CYP1A2, CYP2C19

Bosutinib

CYP3A4

 

Cabozantinib

CYPA34

CYP2C9

Crizotinib

CYP3A4, CYP3A5

CYP2B6

Dabrafenib

CYP3A4

CYP2C8

Dasatinib

CYP3A4

 

Erlotinib

CYP3A4

CYP1A2, CYP1A1

Gefitinib

CYP3A4

CYP2D6

Ibrutinib

CYP3A4

CYP2D6

Imatinib

CYP3A4

CYP1A2, CYP2D6, CYP2C9, CYP2C19

Lapatinib

CYP3A4, CYP3A5

CYP2C19, CYP2C8

Nilotinib

CYP3A4

CYP2C8

Nintedanib

CYP3A4

 

Pazopanib

CYP3A4

CYP1A2, CYP2C8

Ponatinib

CYP3A4

CYP2C8, CYP2D6, CYP3A5

Regorafenib

CYP3A4

 

Ruxolitinib

CYP3A4

CYP2C9

Sorafenib

CYP3A4

 

Sunitinib

CYP3A4

 

Trametinib

-

 

Vandetanib

CYP3A4

 

Vemurafenib

CYP3A4

 

aThe major pathway of metabolism for the kinase inhibitor; bThe minor pathway of metabolism for the kinase inhibitor

CYP3A4 is the most abundant hepatic enzyme and contributes to the metabolism of half of all drugs that undergo oxidative metabolism.3 Of note, grapefruit juice, St John’s Wort and alcohol have an inhibitory and inductive effect, respectively, on CYP3A activity.3

Inhibition or Induction of Cytochrome P450 Enzymes

Compounds (either drugs, foods or herbal supplements) that compete for the metabolism of the same CYP enzyme, or that inhibit or induce CYP enzymes, can lead to drug interactions.2 CYP enzymes can be inhibited by either competitive binding of two substrates at the same enzyme binding site, or by non-competitive inhibition of CYP enzymes by co-administration of an inhibitor with a substrate for the same CYP enzymes. This leads to an increase in exposure (serum area-under-the-curve [AUC]) of the CYP substrate.1 The net effect on the AUC of the CYP substrate depends on the degree of inhibition or induction caused by the co-administered drug.1 Increased or decreased exposure by changes in CYP activity might cause clinically relevant side effects or diminished efficacy.1

Other Factors that can Modify Cytochrome P450 Activity

Other factors that can modulate CYP reactions include genetic variability, age, and comorbidities:3

  • Genetic variability: CYP levels vary between individuals owing to genetic factors. Some CYP isoforms are polymorphic, causing expression of variants with altered catalytic activity, with 20-95% of inter-individual variability in treatment response and toxicity estimated to be attributed to genetic polymorphisms.3,7
  • Age: Elderly patients have reduced overall hepatic metabolic capacity due to a decrease in liver mass, reduced blood flow and decreased enzyme activity.3
  • Comorbidities: Hepatic impairment can cause changes in drug metabolism.3 Also, patients with heart failure or those receiving beta blocker therapy, reduced hepatic blood flow can subsequently affect the rate of liver metabolism.3 In addition, reduced expression and activity of CYP enzymes occurs in renal insufficiency.8

Next page: More about the excretion process

References

  1. van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014; 15: e315-326.
  2. Scripture CD, Figg WD. Drug interactions in cancer therapy. Nat Rev Cancer 2006; 6: 546-558.
  3. Pajares B, Torres E, Trigo JM et al. Tyrosine kinase inhibitors and drug interactions: a review with practical recommendations. Clin Transl Oncol 2012; 14: 94-101.
  4. Bardin C, Veal G, Paci A et al. Therapeutic drug monitoring in cancer--are we missing a trick? Eur J Cancer 2014; 50: 2005-2009.
  5. European Medicines Agency. 2015.
  6. Food and Drug Administration. 2015. 
  7. Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med 2003; 348: 538-549.
  8. Yeung CK, Shen DD, Thummel KE, Himmelfarb J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int 2014; 85: 522-528.

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