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LETTER TO THE EDITOR

More than Polymorphism

Professor of Anesthesiology and Vice-Chairman for Research; Department of Anesthesiology; Penn State College of Medicine; Milton S. Hershey Medical Center; Hershey, PA

In Response:

Dr. Feierman et al. (1) raise several important issues regarding our recent paper (2) reporting the results of our comparative, prospective, double-blind, and randomized study (not observational study, as suggested by the authors) on prevention of postoperative nausea and vomiting (PONV) with granisetron and dolasetron in relation to CYP2D6 genotype.

First is the implication our study postulates that a definite mechanism for the observed lesser efficacy of dolasetron versus granisetron in prophylaxis of PONV is the result of increased metabolism of dolasetron in ultra rapid metabolizers (UM) associated with the duplication of CYP2D6 allele. In fact, the primary objective of this study was to compare the therapeutic effectiveness of these two antiemetics in PONV prophylaxis. We did however include in the Discussion several plausible explanations for the results, but deliberately refrained from offering any definite conclusion regarding the mechanism of the observed differences between granisetron and dolasetron. We clearly stated in the abstract and summary of the discussion that merely "... it is postulated that the differences in the antiemetic efficacy between two investigated 5-HT3 receptor antagonists may be associated with differences in the carrier status for the duplication of the CYP2D6 allele ..."

Second, Feierman et al. offer several interesting observations and suggestions questioning the previously published findings of increased metabolism of ondansetron and tropisetron in carriers of the CYP2D6 allele duplication (3). While I agree that such direct evidence is not convincing at the present time, their discussion clearly identifies the potential difficulties in obtaining the direct proof in the clinical study. For example, when commenting about measuring the plasma concentration of hydrodolasetron in our patients, the authors do not appreciate several facts pertinent to the design of the study:

1. Several of our patients obtained an additional dose of dolasetron in the PACU after episodes of intractable PONV, making the conclusion about the differences in the level of hydrodolasetron meaningless for comparison between carriers of different CYP2D6 allele;
   
2. Time periods and intervals required for serial measurements and pharmacokinetic analysis of hydrodolasetron in 75 of our patients would be both difficult to predict and also technically very challenging (if not impossible) to perform in our particular clinical study design;
   
3. UM for CYP2D6 represent only 5%–8% of all subjects; therefore, the obtained plasma levels of so few patients will be difficult to compare with the much larger number of patients with different types of CYP2D6 allele. In fact, similar difficulties, as stated by the authors, were encountered by Kaiser et al., (3) and precluded the definite conclusion about the mechanism of decreased efficacy of tropisetron in patients in UM group. Furthermore, the suggestion about the lesser effect of CYP2D6 metabolizer status on hydrodolasetron kinetics compared with tropisetron in Li et al. (4) could be challenged by the fact that these observations were not drawn from the studies on UM but merely on poor and extensive (i.e., presenting different metabolic rate for CYP2D6) metabolizers.
   

Finally, the authors offer very valuable additional information about the role of different CYP systems in the metabolism of granisetron, in particular about the potential role (or lack thereof) of interindividual variability in the metabolism of this drug. In light of this evidence, I agree that the role of the "less polymorphic CYP3A4" as the possible explanation for the observed differences in clinical efficacy between dolasetron and granisetron will require further study.

REFERENCES

1. Feierman DE, Trunfio G, Morankar A, et al. More than polymorphism. Anesth Analg 2007;104:1605.[Free Full Text]
2. 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]
3. 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]
4. 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]

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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