Are there any reports of interactions between amphetamine and warfarin?/nRequest for general inform

Fråga: Are there any reports of interactions between amphetamine and warfarin?

Request for general information about drug interactions with amphetamine.

A male patient is treated with amphetamine for narcolepsy. He is also medicating with warfarin and it has proven difficult to achieve a stable therapeutic international normalised ratio.

Sammanfattning: There are no reports of interactions between warfarin and amphetamine. The knowledge of amphetamine metabolism is scarce, and does not allow any theoretical conclusions to be drawn. Amphetamine could possibly increase the risk of warfarin-induced intracerebral haemorrhage by raising the blood pressure.

Difficulties achieving a stable international normalised ratio have been seen in patients carrying mutated alleles of the CYP2C9 gene. On request, genotyping of this gene could be performed at the pharmacological laboratory, Huddinge University Hospital.

Svar: No reports of interaction between the two drugs were found in Medline or standard pharmacological literature. However, a few articles shedding light on the metabolism of amphetamine were encountered (1-3).

The most potent enantiomer of warfarin, S-warfarin, is mainly metabolised by the cytochrome P450 isoenzyme CYP2C9 and most pharmacokinetic interactions involving warfarin are mediated through inhibition, although interactions on the CYP1A2 isoenzyme also have been demonstrated (4). Noteworthy, CYP2C9 is a polymorphic enzyme where different mutations have been shown to reduce dose requirements and make it more difficult to achieve a stable international normalised ratio (5).

Amphetamine is mainly excreted in the urine, unchanged and metabolised (6). Metabolism is through p-hydroxylation of the aromatic ring, N-hydroxylation, deamination and through conjugation (6). CYP2D is known to be involved in human ring hydroxylation of amphetamine (1). However, this pathway is responsible for metabolism of only 5 percent of excreted amphetamine, and in vitro studies indicate that other enzymes than CYP2D are also involved (2). Tricyclics and chlorpromazine reduce the clearance of amphetamine, and this could possibly indicate involvement of CYP2D6 in amphetamine metabolism (6).

In rabbits, CYP2C has been shown to mediate deamination of amphetamine. Deamination is a quantitatively important pathway in man, but it is not known if the human CYP2C isoenzymes CYP2C9 and CYP2C19 are involved in this reaction (3). Among the pharmacokinetic amphetamine interactions presented in Dollery´s "Therapeutic drugs" and the physicians desk reference (tricyclics, acidifying and alkalinising agents, chlorpromazine and MAO inhibitors) there are no obvious interactions on the CYP2C9 level (6-7).

Finally, intracerebral haemorrhage is a well-known complication of amphetamine abuse (8). Although the doses abused are higher than the ones clinically used, hypertension is a known side effect of amphetamine therapy, theoretically increasing the risk of intracranial haemorrhage posed by warfarin treatment (7).

For a brief review of known interactions between amphetamine and drugs other than warfarin, an excerpt from PDR is enclosed (7).