Friday, May 21, 2010

Grapefruit Juice Alters Oxycodone Concentration

Research Update Grapefruit juice alters the concentrations of many CYP3A4 liver enzyme substrates, including some but not all opioid analgesics. A recent investigation verified that oxycodone concentrations are increased if taken in conjunction with grapefruit juice; however, there can be interactions with other agents as well.

Researchers in Finland had 12 healthy volunteers ingest about 7 ounces (200 mL) of grapefruit juice three times a day (about 2.5 cups/day) for 5 days, and 10 mg oxycodone was administered on day 4 [Nieminen et al. 2010]. Grapefruit juice inhibited the first-pass metabolism of oxycodone by CYP3A4 enzymes in the liver; consequently, oxycodone plasma concentrations were significantly increased by 50% and the half-life was extended by 20%. At the same time, the formation of oxymorphone was increased and formation of noroxycodone and nor-oxymorphone metabolites was decreased. Interestingly, the analgesic effect of oxycodone was not affected and the authors further note that “pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice.”

Oxycodone also is metabolized by CYP2D6 liver enzymes. Separate but related research from this same group in Finland found that inhibition of CYP2D6 alone, such as by paroxetine administration, had little influence on oral oxycodone metabolism; however, if both CYP2D6 and CYP3A4 pathways are inhibited (eg, by concurrent paroxetine and itraconazole administration), the exposure to oxycodone is substantially increased [Gronlund et al. 2010].

COMMENT: Single-dose pharmacokinetics studies of this sort have inherent limitations and the applicability to chronic daily dosing with oxycodone may be less straightforward. Still, it has been well-established that many opioid analgesics (with the exception of morphine, hydromorphone, and oxymorphone) are metabolized via CYP450 liver enzymes, including CYP3A4 and/or CYP2D6, and multiple enzymes in the case of methadone [see Smith 2009 for discussion]. It might be erroneously believed that the coadministration of CYP inhibitors, including grapefruit juice, might be used to boost opioid analgesic effects without a need for increasing the opioid dose. However, these studies suggest that such practice may not provide added analgesia and could exacerbate side effects, including the possibility of overdose. The effects of either CYP450 inhibitors or inducers on opioid metabolism can be variable and unpredictable [see Flockhart for lists of inducers and inhibitors].
SIDE NOTE: Cafestol (found in unfiltered coffee drinks, such as French-press, Turkish, or Greek coffee) can inhibit CYP3A4 and thereby might diminish the metabolism and analgesic effects of oxycodone, tramadol, fentanyl, and possibly methadone. The daily amount of these coffee drinks to have this effect has not been determined but patients might be advised against consuming such beverages if they are on opioid therapy.
> Flockhart DA. Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine [
available here].
> Gronlund J, Saari TI, Hagelberg NM, et al. Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone. Br J Clin Pharmacol. 2010 online ahead of print [
abstract here]
> Nieminen TH, Hagelberg NM, Saari TI, et al. Grapefruit Juice Enhances the Exposure to Oral Oxycodone. Basic Clin Pharmacol Toxicol. 2010(Apr 15) online ahead of print [
abstract here]
> Smith HS. Opioid Metabolism. Mayo Clin. Proc. 2009(Jul);84(7):613-624 [
full article here].