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LETTER TO THE EDITOR

More than Polymorphism

Maimonides Medical Center; dfeierman{at}nyc.rr.com (Feierman, Trunfio, Morankar) Division of Clinical and Translational Research; Department of Anesthesiology; Washington University; St. Louis, MO (Kharasch)

To the Editor:

We wish to address several issues concerning the recent findings by Janicki et al. (1) that variability in CYP 2D6 was responsible for variability in the clinical response to dolasetron.

First, Janicki et al. postulate that dolasetron antiemetic efficacy was related to CYP2D6, with decreased efficacy attributed to duplication of the CYP2D6 allele and thus more rapid CYP2D6-catalyzed metabolism and elimination of the active metabolite hydrodolasetron. It is surprising that the authors would postulate a pharmacokinetic mechanism for variability in response without measuring plasma hydrodolasetron concentrations. Thus, readers are left with an inference of reduced plasma concentrations based on genotypic analysis, but no data to confirm this inference.

Second, Janicki et al. do not offer any evidence for accelerated hydrodolasetron elimination due to duplication of the CYP2D6 allele. While they do cite, to support their conclusions, accelerated tropisetron elimination due to CYP2D6 duplication (2), available data suggest a lesser effect of CYP2D6 metabolizer status on hydrodolasetron kinetics compared with tropisetron (3). While they also cite, to support their conclusions, diminished efficacy of tropisetron in ultrarapid metabolizers (4), this same manuscript reported that there was no difference in tropisetron plasma concentrations in the ultrarapid metabolizers.

Third, Janicki et al. suggest that greater granisetron efficacy may occur because this drug is instead metabolized by the "less polymorphic CYP3A4 system." Although granisetron is metabolized to 9'-desmethylgranisetron by CYP3A4, the more important metabolic pathway at clinically relevant concentrations is 7-hydroxylation, which is catalyzed by CYP1A (5,6). Furthermore, while CYP3A4 is not polymorphically expressed, there exists significant interindividual variability (7). Additionally, another pertinent enzyme in the adult CYP3A system, CYP3A5, is highly polymorphically expressed and metabolizes many CYP3A4 drugs. The role of CYP3A5 in granisetron pharmacokinetics and its efficacy has not been reported. More importantly, however, CYP inhibition did not affect granisetron kinetics (8). Thus, it might not matter whether there is or is not CYP3A polymorphism.

While Janicki et al. reported a thorough observational outcome study, and such studies are highly useful, conclusions regarding mechanisms should be supported by adequate data.

REFERENCES

1. Janicki PK, Schuler HG, Jarzembowski TM, Rossi M II. Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype. Anesth Analg 2006;102:1127–33.[Abstract/Free Full Text]
2. Kim MK, Cho JY, Lim HS, et al. Effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. Eur J Clin Pharmacol 2003;59: 111–6.[Web of Science][Medline]
3. Li SX, Pequignot E, Panebianco D, et al. Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers. J Clin Pharmacol 2006;46:792–801.[Abstract/Free Full Text]
4. Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5- hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002; 20:2805–11.[Abstract/Free Full Text]
5. Bloomer JC, Baldwin SJ, Smith GJ, et al. Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron. Br J Clin Pharmacol 1994;38:557–66.[Web of Science][Medline]
6. Nakamura H, Ariyoshi N, Okada K, et al. CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes. Curr Drug Metab 2005;6:469–80.[Web of Science][Medline]
7. Kharasch ED, Thummel KE. Human alfentanil metabolism by cytochrome P450 3A3/4. An explanation for the interindividual variability in alfentanil clearance? Anesth Analg 1993;76:1033–9.[Abstract/Free Full Text]
8. Youlten L. The effect of repeat dosing with cimetidine on the pharmacokinetics of intravenous granisetron in healthy volunteers. J Pharm Pharmacol 2004;56:169–75.[Web of Science][Medline]

This article has been cited by other articles:

				P. K. Janicki More than Polymorphism Anesth. Analg., June 1, 2007; 104(6): 1605 - 1606. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Feierman, D. E. Articles by Kharasch, E. Search for Related Content PubMed Articles by Feierman, D. E. Articles by Kharasch, E.

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999