The Sweet Effect of Honey on Drug Metabolism

The well-documented effects ofgrapefruit juice on the pharmacokineticsof many drugs haveraised awareness that foods can havespecific effects on cytochrome P-450drug-metabolizing enzymes and drugtransporters such as P-glycoprotein.Recently, reports have described theeffect of honey on cytochrome P-450isozymes in healthy patients and animals.Effect of Honey on CYP450IsozymesIn a recent study, 12 healthy patientswere tested for activity of CYP2D6,CYP2C19, and CYP3A4 after 7 days ofhoney administration.1

Dextromethorphan was given to testfor CYP2D6, proguanil to test forCYP2C19, and endogenous 6-betahydroxycortisolexcretion as a markerfor CYP3A4 activity. There were nochanges in dextromethorphan orproguanil?-suggesting that honey ingestiondoes not affect the activity ofCYP2D6 or CYP2C19.

The excretion of endogenous 6-betahydroxycortisolwas significantly increased,however?suggesting an increasein CYP3A4 activity. The substancesin honey that might beresponsible for the increased CYP3A4activity are not known.

The evidence of increased CYP3A4activity was consistent, occurring in 11 ofthe 12 patients. The study also found amarked difference in the magnitude ofthe effect, as is usually the case in drug interactionstudies; 1 participant had adoubling of the marker, and another hada 3-fold increase.

These results suggest that some peoplemay have a marked increase inCYP3A4 activity, but actual drug?druginteraction studies will be needed to confirmthis possibility. Of course, honey isnot a standardized substance, and it ispossible that different types of honeywould have varying effects on drugmetabolism.Effect of Honey on CYP3A4SubstratesAssuming that the CYP3A4 markerstudy described above reflects anincrease in CYP3A4 activity, one wouldexpect regular ingestion of honey toreduce the efficacy of drugs metabolizedby CYP3A4, at least in some patients.Although animal studies have foundreduced plasma concentrations ofCYP3A4 substrates (diltiazem) withrepeated doses of honey,2 this findingdoes not necessarily apply to humans.Nonetheless, until more evidence isavailable, it would be prudent to considerregular honey ingestion as a possiblecause for a reduced therapeutic effect ofdrugs metabolized by CYP3A4.Effect of Honey on Carbamazepine

Based on the evidence of increasedCYP3A4 activity described above, onewould expect reduced plasma concentrationsof drugs metabolized byCYP3A4, such as carbamazepine. Thisdrug is itself a potent inducer of CYP3A4,however, and it can enhance its ownmetabolism over time. Thus, it is not clearthat any CYP3A4 induction due to theingestion of honey would add to theinduction already occurring due to carbamazepine.

A study of 10 healthy patients foundno effect from a single 30-mL dose ofhoney on carbamazepine pharmacokinetics,3 but enzyme induction would notbe expected after a single administrationof an enzyme inducer.Indeed, a study in rabbits foundincreased clearance of carbamazepinewith 7 days of honey, but no effect with 1day of honey.4 Therefore, this negativesingle-dose study did not adequatelyassess the effect of honey on carbamazepine.Overall, at this time it does notappear necessary for patients taking carbamazepineto be warned about ingestinghoney.Summary

Preliminary evidence from humanstudies of honey on CYP450 activity suggeststhat honey may increase CYP3A4activity but may not affect the activity ofCYP2D6 or CYP2C19. It appears thatincreased CYP3A4 activity requires regularingestion of honey for several days ormore, and that occasional ingestion isunlikely to significantly affect drug plasmaconcentrations. Pending additionalinformation, one should consider honeyingestion as a possible cause of alteredresponse to drugs metabolized byCYP3A4.

Drs. Horn and Hansten are both professorsof pharmacy at the Universityof Washington School of Pharmacy.For an electronic version of this article,including references if any, visitwww.hanstenandhorn.com.

References

1. Tushar T, Vinod T, Rajan S, Shashindran C, Adithan C. Effect of honey on CYP3A4, CYP2D6 and CYP2C19 enzyme activity in healthy human volunteers. Basic Clin Pharmacol Toxicol. 2007;100:269-272.

2. Koumaravelou K, Adithan C, Shashindran C, Asad M, Abraham BK. Influence of honey on orally and intravenously administered diltiazem kinetics in rabbits. Indian J Exp Biol. 2002;40:1164-1168.

3. Malhotra S, Garg SK, Dixit RK. Effect of concomitantly administered honey on the pharmacokinetics of carbamazepine in healthy volunteers. Methods Find Exp Clin Pharmacol. 2003;25:537-540.

4. Koumaravelou K, Adithan C, Shashindran C, Asad M, Abraham BK. Effect of honey on carbamazepine kinetics in rabbits. Indian J Exp Biol. 2002;40:560-563.