Polymorphic CYP2D6 mediates O -demethylation of the opioid analgesic tramadol

Paar, W. D.; Poche, S; Gerloff, J.; Dengler, H. J.

doi:10.1007/s002280050368

Cited by 138 publications

(87 citation statements)

References 7 publications

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“…The next morning (day 1 after hospital discharge), the parents found him lethargic and brought him back to our center. On arrival at the emergency department, he was comatose (pediatric Glasgow coma scale score of 8) with pin-point pupils, minimal respiratory effort, frequent 9 Genotyping of CYP2D6 revealed the presence of 3 functional alleles corresponding to CYP2D6*2 3 2 / CYP2D6*2 genotype, consistent with an ultrarapid metabolism.…”

Section: Case Reportmentioning

confidence: 99%

A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol

Orliaguet¹,

Hamza²,

Couloigner

et al. 2015

Pediatrics

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We discuss a case of severe respiratory depression in a child, with ultrarapid CYP2D6 genotype and obstructive sleep apnea syndrome, after taking tramadol for pain relief related to a day-case tonsillectomy.Pain management is challenging after ambulatory tonsillectomy in children and has become more so since the publication of restrictions on the use of codeine for pain relief in children. 1 These restrictions followed reports of severe and fatal respiratory depression in children after the use of codeine for pain relief. [2][3][4][5][6]

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Section: Case Reportmentioning

confidence: 99%

A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol

Orliaguet¹,

Hamza²,

Couloigner

et al. 2015

Pediatrics

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“…In most countries, tramadol is the only clinically available non -scheduled opioid. The marketed tramadol is a racemic mixture containing 50% of (+) tramadol and 50% of (-) tramadol, and is mainly metabolized to O-desmethyltramadol (M1) and N-desmethyltramadol (M2) by the cytochromes P450 CYP2B6/CYP3A4 and CYP2D6, respectively [1,2]. The pharmacokinetic and pharmacodynamic properties of tramadol are known to be both enantioselective and influenced by the CYP2D6 phenotype [1,[3][4][5][6].…”

mentioning

confidence: 99%

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

Elkalioubie

Allorge

Robriquet

et al. 2011

Eur J Clin Pharmacol

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“…For example, it shows a moderate affinity for -opioid receptors (Lai et al, 1996), and individuals with an impaired (ϩ)-M1 formation (poor metabolizers) showed a decreased degree of analgesia after T administration (Poulsen et al, 1996). Since (ϩ)-M1 formation in humans is governed by the enzyme CYP2D6 (Paar et al, 1992(Paar et al, , 1997, the identification of factors affecting the CYP2D6 activity jpet.aspetjournals.org and establishing the relationship between such activity and analgesia are required to optimize the use of T.…”

Section: Discussionmentioning

confidence: 99%

“…The relative role of the enantiomers of T and M1 in anal-gesia after T administration is an issue that still has to be addressed properly for at least two main reasons: first, data from the literature suggest that (ϩ)-M1 is the main agent responsible for T effects (Poulsen et al, 1996), and second, the enzyme CYP2D6 is involved in M1 formation (Paar et al, 1992(Paar et al, , 1997. Taking into account the fact that this enzyme is polymorphically expressed (Bertilsson et al, 1992) and eventually can be inhibited (Abdel-Rahman et al, 1999;, situations where the CYP2D6 activity is decreased are likely to occur, and therefore the relationship between the degree of enzyme activity and analgesic response needs to be established.…”

mentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity

Garrido

Sayar²,

Segura³

et al. 2003

J Pharmacol Exp Ther

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In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (ϩ)-tramadol [(ϩ)-T] has been explored in rats. Male Wistar rats were infused with (ϩ)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (ϩ)-T, and (ϩ)-O-demethyltramadol [(ϩ)-M1], and measuring antinociception. Pharmacokinetics of (ϩ)-M1, but not (ϩ)-T, was affected by Q pretreatment: early after the start of (ϩ)-T infusion, levels of (ϩ)-M1 were significantly lower (P Ͻ 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (ϩ)-M1. In fact, results from another experiment where (ϩ)-M1 was given in the presence and in absence of Q showed that (ϩ)-M1 elimination clearance (CL ME0 ) was significantly lower (P Ͻ 0.05) in animals receiving Q. Inhibition of both (ϩ)-M1 formation clearance (CL M10 ) and CL ME0 were modeled by an inhibitory E MAX model, and the estimates (relative standard error) of the maximum degree of inhibition (E MAX ) and IC 50 , plasma concentration of Q eliciting half of E MAX for CL M10 and CL ME0 , were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (ϩ)-T was negligible and (ϩ)-M1 was responsible for the observed effects, which depend linearly on (ϩ)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (ϩ)-T administration.Tramadol (T) is a safe and effective analgesic used during the last two decades in the treatment of several types of pain (Rhoda et al., 1993;Raffa et al., 1995). Despite its long-term use, the understanding and prediction of the time course of its pharmacological effects are still hampered by the presence of active metabolites and the coexistence of opioid and nonopioid mechanisms. In fact, T is administered as a racemic mixture of two enantiomers, (ϩ)-T and (Ϫ)-T, which are metabolized in the liver forming, among others, the two main, respectively. Data from literature suggest that (ϩ)-enantiomers show opioid properties, while (Ϫ)-enantiomers are able to inhibit the uptake of norepinephrine. This duality of action makes T an atypical opioid (Raffa et al., 1992;Raffa and Friderichs, 1996).Recently the antinociceptive properties of the two active metabolites of T, (ϩ)-M1 and (Ϫ)-M1, have been evaluated in the pharmacokinetic/pharmacodynamic (pk/pd) perspective in the rat. The results showed that (ϩ)-M1, in accord with its -opioid receptor agonist properties (Lai et al., 1996), was able to produce maximum antinociception in the tail-flick test; however, when (Ϫ)-M1, a monoamine re-uptake inhibitor (Frink et al., 1996), was given alone, no significant effects were found . However, Garrido et al., 2000 showed that in the presence of ...

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Polymorphic CYP2D6 mediates O -demethylation of the opioid analgesic tramadol

Cited by 138 publications

References 7 publications

A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol

A Case of Respiratory Depression in a Child With Ultrarapid CYP2D6 Metabolism After Tramadol

Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

Pharmacokinetic/Pharmacodynamic Modeling of the Antinociceptive Effects of (+)-Tramadol in the Rat: Role of Cytochrome P450 2D Activity

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