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
- Pharmaco-genomics
Drug Interacting Gene/Enzyme Allele name Genotypes Defining change(s) Type(s) Description Details Methadone Cytochrome P450 2B6
Gene symbol: CYP2B6
UniProt: P20813CYP2B6*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: P20813CYP2B6*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: P20813CYP2B6*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: P20813CYP2B6*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: P20813CYP2B6*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: P20813CYP2B6 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: P20813CYP2B6 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: P20813CYP2B6 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: P20813CYP2B6 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: P08684CYP3A4*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