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DRUG INTERACTIONS AND DONEPEZIL

2000; Wiley; Volume: 48; Issue: 5 Linguagem: Inglês

10.1111/j.1532-5415.2000.tb05016.x

1532-5415

Carlos Rojas‐Fernandez, Charles Fisher,

Analytical Methods in Pharmaceuticals

To the Editor: We read with interest the very informative and thought provoking case report by Dr. Carrier — “Donepezil and paroxetine: Possible drug interaction” — wherein Dr. Carrier hypothesizes that inhibition of cytochrome P-450 (CYP 450) 2D6 by paroxetine may have been responsible for donepezil toxicity observed in two of her patients.1 Although we agree with Dr. Carrier's comments, we would like to contribute additional putative explanations for the observed effects. Various pharmacokinetic facts should be considered when attempting to ascertain possible explanations to Dr. Carrier's observations. Donepezil seems to be metabolized by two isoforms of CYP 450, namely 2D6 and 3A4, as well undergoing glucuronidation.2 CYP 2D6 generally accounts for 5 to 10% of all CYP activity in any patient, and 5 to 10% of white persons lack the functional 2D6 isoenzyme and are thus classified as poor metabolizers (PMs).3 Furthermore, CYP 3A4 accounts for 60% of CYP 450 in the liver and 70% of CYP in enterocytes found in the gut wall, is responsible for first pass metabolism, and is expressed variably (10- to 40-fold) across individuals.4 CYP 3A4 can be inhibited by various drugs (as can CYP 2D6) as well as by grapefruit juice.4 To complicate matters further, recent literature has suggested that inhibition of intestinal p-glycoprotein may be the mechanism behind some drug interactions thought previously to be secondary to inhibition of intestinal CYP 3A4.5 As CYP 3A4 is a major contributor to total hepatic CYP 450 activity, it is possible that for drugs such as donepezil, CYP 3A4 might be the primary and most relevant metabolic pathway and that CYP 2D6 would contribute little to the overall metabolism of donepezil. It should be noted, however, that the isoform primarily responsible for the metabolism of donepezil (i.e., 2D6 or 3A4) is not yet known. Results from a recent drug interaction study that evaluated the effects of cimetidine (a nonspecific CYP inhibitor) and ketoconazole (a CYP 3A4 inhibitor) on the pharmacokinetics and tolerability of donepezil indicated no significant changes in the tolerability or kinetic profile of donepezil when administered with cimetidine.6 Co-administration with ketoconazole resulted in nonsignificant changes in pharmacokinetics on Day 1 of therapy, whereas significant increases in maximum drug concentration (26.8%) and area under the curve (26.4%) were noted after 7 days of therapy, and tolerability was unchanged. That the observed changes on Day 7 were smaller than those produced by co-administration of ketoconazole with other drugs metabolized by the CYP 3A4 pathway might be attributable to the fact that donepezil is also metabolized by CYP 2D6.6 Therefore, an alternative phamacokinetic explanation for the effects observed by Dr. Carrier could be that these patients may have had lower than average CYP 3A4 activity, either as a normal variant or secondary to other medications/substances that are CYP 3A4 inhibitors in addition to 2D6 inhibition by paroxetine. However, the authors did not list concomitant medications that these patients were receiving, and, thus, it is unclear whether they were taking agents known to alter CYP3A4 activity. We also do not have the benefit of having serum levels of donepezil from these case reports, which would help clarify the picture (we acknowledge, however, that these are not routinely available or used in practice), nor do we know whether these patients had normal CYP 2D6 activity or if they were PMs. Additional potential interactions involving other polymorphic enzymes could be invoked to explain these patient responses. For example, donepezil is also glucuronidated; therefore, a polymorphism such as the UGT1A1 locus (Gilbert's syndrome, which is observed in 5 to 10% of the population) could produce higher levels of donepezil in some individuals, thus making them more susceptible to drug interactions.7 Another less appreciated polymorphism is that occurring in acetylcholinesterase.8 Although donepezil does not interact strongly with butyrylcholinesterase, the effect the acetylcholinesterase polymorphism has on donepezil activity is unknown. Combinations of polymorphisms in both metabolism and acetylcholinesterases could complicate this seemingly simple drug-drug interaction. It is clear that additional human studies (metabolic and drug-drug interaction studies) are needed in order to understand better the potential for drug interactions with donepezil. Indeed, it is unknown whether simply inhibiting CYP 2D6 with paroxetine would result in significant increases in plasma levels of donepezil as this potential drug interaction has not been adequately studied. Additional drug interaction studies would provide useful data to clinicians who use this drug with other psychotropics, a common necessity in this patient group. Finally, in the worst case scenario, the observed effects may be congruent with recent case reports of worsening behavioral symptoms with donepezil.9,10 Although these observations may not make inherent sense, they demonstrate that there is much to learn about how these drugs affect different patients. It is also possible (though unlikely) that the nausea and vomiting noted in the first patient were the result of the normally occurring GI intolerance noted in clinical trials. For example, in a 12-week study of donepezil, the incidence of nausea/vomiting and diarrhea was 10% compared with 5% and 3% for placebo.11 To this end, we agree with Dr. Carrier that clinicians must always be cautious and “keep their eyes open” whenever a new psychotropic medication is prescribed to patients with Alzheimer's disease who are receiving donepezil, or vice versa. Indeed, her case report serves as a very important reminder of how unpredictable drug interactions can be and that we should not complacent when using psychotropic medications.