Monograph
N02AX02 - Tramadol |
Propably not porphyrinogenic |
PNP |
Rationale
Tramadol is metabolised by the cytochrome P450 isoenzymes, CYP 3A4 and CYP 2D6, but it is not an inducer or an inhibitor of the enzymes. Probably low PXR-affinity of the parent substance. Physiological effects on PXR/CAR-activation by serotonergic action is probably without relevance to acute porphyria. There are 12 reports (per February 2010) of safe use in carriers of acute porphyria.
Chemical description
(±)-trans-2-Dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride. M=300. Terminal tertiary amine function.
Therapeutic characteristics
Tramadol is used for moderate to severe pain. It is a non-selective, complete agonist of µ-, δ- and κ opioid receptors with a higher affinity for µ-receptors. Other mechanisms contributing to the analgesic effect are the inhibition of the neural noradrenalin reuptake and an enhanced release of serotonine. Common confounding side-effects are nausea, vomiting, obstipation. Overdosage may give cardiovascular collapse or respiratory arrest.
Hepatic exposure
Probably significant.
Metabolism and pharmacokinetics
In humans the cytochrome P450 isoenzymes, CYP 3A4 and CYP 2D6 are involved in the metabolism of tramadol. It is a substrate of these enzymes (Rendic 2002 ; Martindale 2009)and clinical interaction studies give evidence of absence of significant capacity for CYP-induction or inhibition. Tramadol is mainly metabolised by means of N- and O-demethylation and conjugation of the O-demethylation products with glucuronic acid. Only O-desmethyltramadol is pharmacologically active (The electronic Medicines Compendium (eMC),UK). On oral administration it has relatively low first-pass effect, maximum of 30 per cent. High tissue affinity Vdb= around 203 l. After N-demethylation via CYP 3A4, the principal pharmacodynamically active O-demethylated metabolite is generated by CYP 2D6, which exhibits genetic polymorphism (Martindale 2009). The N-methylated parent drug is water soluble and thus probably of relatively low PXR-affinity.
Preclinical data
Observed to give rise to porphyrin accumulation in chicken embryo system, (Lambrecht,1999).
Personal communication
S.Thunell 2004, patient inquiry: tolerated (n=1).
Published experience
No observations of clinical porphyrogenicity published.
IPNet drug reports
Uneventful use reported in 15 patients with acute porphyria.
References
| # |
Citation details |
PMID |
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| * | Scientific articles |
| 1. |
Lambrecht et al, Biochem Pharmacol 1999, Effects of antihypertenand analgesics on hepatic porphyrin accum, implic for clin porphyria.
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| 2. |
Rendic S et al, Drug Metabolism Reviews 2002, Summary of information on human cyp enzymes Human P40 metabolism data.
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| * | Drug reference publications |
| 3. |
Martindale 2009 online.
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| * | Drug interaction databases |
| 4. |
LEXI-COMP online.
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| * | Summary of Product Characteristics |
| 5. |
The electronic Medicines Compendium (eMC),UK.
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