Is There a Role for Pharmacogenetics in the Dosing of Fentanyl?

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects

“…Fentanyl is metabolised in the liver by two isoforms of the cytochrome P450 (CYP) complex, CYP3A4 and CYP3A5, which are responsible for its N‐dealkylation forming the non‐toxic and inactive metabolite norfentanyl. Only a small amount of drug (<1%) can be metabolised by N‐dealkylation, amide hydrolysis or alkyl hydroxylation leading to the inactive metabolites hydroxynorfentanyl and despropionylfentanyl . Although it is mostly excreted in urine, it can be eliminated in faeces and by exhalation …”

“…CYP3A5 is a member of the CYP3A family whose most common non‐functional allele is CYP3A5 *3. This allele causes alternative splicing, thus producing a truncated protein and higher levels of metabolites . Regarding their effect on fentanyl, CYP3A5 *3 is known to cause an increase in systemic exposure to the drug, whereas there is no evidence of any relationship between this effect and CYP3A4 polymorphisms …”

“…Only a small amount of drug (<1%) can be metabolised by N-dealkylation, amide hydrolysis or alkyl hydroxylation leading to the inactive metabolites hydroxynorfentanyl and despropionylfentanyl. 11 Although it is mostly excreted in urine, 12 it can be eliminated in faeces and by exhalation. 13 Since CYP3A4 is the main enzyme responsible for the metabolism of fentanyl, variants in its coding gene have been studied in association with fentanyl's disposition.…”

“…This allele causes alternative splicing, thus producing a truncated protein and higher levels of metabolites. 11,16 Regarding their effect on fentanyl, CYP3A5*3 is known to cause an increase in systemic exposure to the drug, whereas there is no evidence of any relationship between this effect and CYP3A4 polymorphisms. 11 The ABCB1 gene is highly polymorphic, with at least 38 variants described.…”

“…11,16 Regarding their effect on fentanyl, CYP3A5*3 is known to cause an increase in systemic exposure to the drug, whereas there is no evidence of any relationship between this effect and CYP3A4 polymorphisms. 11 The ABCB1 gene is highly polymorphic, with at least 38 variants described. 17 Although some of these polymorphisms have shown an effect on fentanyl pharmacokinetics 18 and the incidence of adverse effects, 7,19 there is great controversy about their influence.…”