Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics.

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Ahmad T, Valentovic MA, Rankin GO

Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics.

Biochem Pharmacol. 2018 Jul;153:196-204. doi: 10.1016/j.bcp.2018.02.020. Epub 2018 Feb 16.

PubMed ID

29458047 [ View in PubMed

]

Abstract

Methadone is a synthetic, long-acting opioid with a single chiral center forming two enantiomers, (R)-methadone and (S)-methadone, each having specific pharmacological actions. Concentrations of (R)- and (S)-methadone above therapeutic levels have the ability to cause serious, life-threatening, and fatal side effects. This toxicity can be due in part to the pharmacogenetics of an individual, which influences the pharmacokinetic and pharmacodynamic properties of the drug. Methadone is primarily metabolized in the liver by cytochrome P450 (CYP) enzymes, predominately by CYP2B6, followed by CYP3A4, 2C19, 2D6, and to a lesser extent, CYP2C18, 3A7, 2C8, 2C9, 3A5, and 1A2. Single nucleotide polymorphisms (SNPs) located within CYPs have the potential to play an important role in altering methadone metabolism and pharmacodynamics. Several SNPs in the CYP2B6, 3A4, 2C19, 2D6, and 3A5 genes result in increases in methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance. In particular, carriers of CYP2B6*6/*6 may have a greater risk for detrimental adverse effects, as methadone metabolism and clearance are diminished in these individuals. CYP2B6*4, on the other hand, has been observed to decrease plasma concentrations of methadone due to increased methadone clearance. The involvement, contribution, and understanding the role of SNPs in CYP2B6, and other CYP genes, in methadone metabolism can improve the therapeutic uses of methadone in patient outcome and the development of personalized medicine.

DrugBank Data that Cites this Article

Drugs

Methadone

Pharmaco-genomics

Drug	Interacting Gene/Enzyme	Allele name	Genotypes	Defining change(s)	Type(s)	Description	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6*6	Not Available	516G >T (rs3745274)	pgx review	The presence of the rs3745274 minor allele (CYP2B6 515G > T) has been found to affect methadone pharmacokinetics. It reduces CL/F by up to 20% for S-methadone only and reduces (R)- and (S)-methadone N-demethylation,	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6*4	Not Available	c.785A>G (rs2279343)	pgx review	The presence of the rs2279343 allele (CYP2B6 785A>G) amplifies CYP2B6 activity and has been found to increase methadone metabolism and clearance.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6*2	Not Available	c.64C > T (rs8192709)	pgx review	The presence of the rs8192709 allele has been found to result in a lower metabolic ratio of [Methadone]/[EDDP] in heterozygotes.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6*9	Not Available	516G>T (rs3745274)		The presence of the rs3745274 allele (CYP2B6 516G>T) has been shown to reduce CYP2B6 activity, increase (R,S)-methadone plasma levels, and reduce (R)- and (S)-methadone N-demethylation.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6*11	Not Available	136A > G (rs35303484)	pgx review	The presence of the rs35303484 allele (CYP2B6 135A>G) has been shown to increase (S)-methadone plasma levels and decrease clearance.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6 3′UTR	Not Available	c.*1355A > G (rs707265)	pgx review	The presence of the rs707265 allele (CYP2B6 c.*1355A>G) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6 3′UTR	Not Available	c.*1277A > T (rs1038376)	pgx review	The presence of the rs1038376 allele (CYP2B6 c.*1277A > T) has been shown to increase the [(S)-MTD/MTD Dose] plasma ratio and reduce (S)-MTD clearance.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6 intron 1	Not Available	c.172–468 T > G (rs10403955)	pgx review	The presence of the rsl0403955 allele (c.172–468 T>G) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.	Details
Methadone	Cytochrome P450 2B6 Gene symbol: CYP2B6 UniProt: P20813	CYP2B6 intron 5	Not Available	c.923–197T > C (rs2279345)		The presence of the rs2279345 allele (CYP2B6 c.923–197T>C) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.	Details
Methadone	Cytochrome P450 3A4 Gene symbol: CYP3A4 UniProt: P08684	CYP3A4*1B	Not Available	−392A > G (rs2740574)	pgx review	The presence of the rs2740574 allele (CYP3A4 −392A>G) has been shown to increase (S)-methadone plasma levels.	Details