Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.

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Crews KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, Haidar CE, Shen DD, Callaghan JT, Sadhasivam S, Prows CA, Kharasch ED, Skaar TC

Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update.

Clin Pharmacol Ther. 2014 Apr;95(4):376-82. doi: 10.1038/clpt.2013.254. Epub 2014 Jan 23.

PubMed ID

24458010 [ View in PubMed

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Abstract

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

DrugBank Data that Cites this Article

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*3	Not Available	2549delA (rs35742686)	Effect Directly Studied	The presence of this polymorphism in CYP2D6 results in non-functioning enzyme variant and may be associated with reduced drug mtabolism or reduced therapeutic response when treated with codeine.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*4	Not Available	A allele (rs3892097)	Effect Directly Studied	The presence of this polymorphism in CYP2D6 is associated with poor metabolism of codeine.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*5	Not Available	Whole-gene deletion	Effect Directly Studied	The presence of this polymorphism in CYP2D6 is associated with poor metabolism of codeine and lack of therapeutic response from codeine.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*6	(-;T) / (-;-)	1707delT (rs5030655)	Effect Directly Studied	The presence of this polymorphism in CYP2D6 is associated with poor metabolism of codeine.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*7	Not Available	2935A>C (rs5030867)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*8	Not Available	1758G>T (rs5030865)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*11	Not Available	883G>C (rs5030863)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*12	Not Available	124G>A (rs5030862)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*13	Not Available	CYP2D7/2D6 hybrid gene structure	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*14A	Not Available	1758G>A (rs5030865)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*15	Not Available	137insT, 137_138insT	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*19	Not Available	2539_2542delAACT (rs72549353)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*20	Not Available	1973_1974insG (rs72549354)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*21	Not Available	2573insC	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*31	Not Available	-1770G>A -1584C>G -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*36	Not Available	100C>T (rs1065852) -1426C>T variable number of A’s in the region -1258 to -1237a show all 9 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*38	Not Available	2587_2590delGACT (rs72549351)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*40	Not Available	1863_1864ins(TTT CGC CCC)2 (rs72549356)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*42	Not Available	3259_3260insGT (rs72549346)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*44	Not Available	2950G>C	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*47	Not Available	100C>T (rs1065852) -1426C>T -1235A>G show all 8 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*51	Not Available	-1584C>G -1235A>G -740C>T show all 9 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*56	Not Available	3201C>T (rs72549347)	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*57	Not Available	100C>T 310G>T 843T>G show all 10 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*62	Not Available	4044C>T	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*68A	Not Available	-1426C>T -1235A>G -1000G>A show all 6 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*68B	Not Available	Similar but not identical switch region compared to CYP2D668A. Found in tandem arrangement with CYP2D64.	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*69	Not Available	2988G>A (rs28371725) -1426C>T -1235A>G show all 17 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*92	Not Available	1995delC	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*100	Not Available	-1426C>T -1235A>G -1109C>T show all 15 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*101	Not Available	-1426C>T -1235A>G -1000G>A show all 14 …	Effect Inferred	Poor drug metabolizer. Lack of efficacy. For individual with two non-functional alleles, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*1XN	Not Available	Normal allele duplicated.	ADR Inferred	Ultra-rapid drug metabolizer. Risk of toxicity, alternative drug recommended.	Details
Codeine	Cytochrome P450 2D6 Gene symbol: CYP2D6 UniProt: P10635	CYP2D6*2XN	Not Available	2850C>T (rs16947) 4180G>C (rs1135840) 1661G>C duplicated	ADR Inferred	Ultra-rapid drug metabolizer. Risk of toxicity, alternative drug recommended.	Details