In Response

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We thank Drs Brocks and Davies1 for their interest in our article and appreciate the opportunity to address their queries. First, we regret an error in units in Table 2 (of our article) for volume of distribution (μL/g) and clearance (μL/g*min), as well as in Figure 2 (of our article2) for area under the curve for 150 minutes (AUC150) (μg*min/mL). In spite of these unit errors, the statistical differences and conclusions based on our data remain unchanged.
In Figure 1 in the original article, each time point was not dose-normalized for the wild-type (WT) mice. Figure 1 supplied in this response shows dose-normalized to 80 mg/kg made at each time point for the WT mice groups receiving 20 and 40 mg/kg morphine dosing, as well as the other groups, all of whom received 80 mg/kg. Dose-adjusted changes in AUC150 between the mice strains are shown in Figure 2 in the original article. At the request of the reviewer, we have provided the concentration versus time data for morphine and the metabolite M3G (Figure 2 of this article), where the WT group shows the dose-normalized mean of mice receiving 20, 40, and 80 mg/kg morphine dosing. The initial retro-orbital blood sampling followed the intraperitoneal morphine injection as rapidly as possible, <1 minute, but still a long enough delay such that some “0” minute samples were nonzero.
Originally, we excluded the 100 mg/kg WT animals from the combined WT group, as indicated in the article, because the WT mice, much lower in weight than the obese mice (approximately 5 g less) who received a 100 mg/kg morphine dose—a hydrophilic drug recommended to be dosed based on ideal body weight3—received a much higher intravascular dose than the obese mice receiving 80 mg/kg and not unexpectedly contributed more outliers than the other WT mice dose groups included in the analysis. The WT mice groups in our primary analysis, therefore, included only mice receiving 20, 40, and 80 mg/kg morphine dosing. If we compare only the WT mice receiving the exact same dose as the obese and leptin replacement mice (80 mg/kg of morphine), all the same pharmacokinetic parameters were statistically different as when the 20, 40, and 80 mg/kg doses were combined for the comparison described in the original article. So, whether pooled across WT dose groups or simply comparing the 80 mg/kg WT group, the resulting PK parameter differences observed between WT and the leptin-deficient ob/ob group were reversed when leptin was readministered, which was the primary conclusion described in our original article.
Lastly, we agree that changes in morphine-3-glucuronide clearance may affect the morphine-3-glucuronide/morphine ratio, but we believe the combination of observed differences in morphine sulfate pharmacokinetics (longer T1/2, increased AUC150 and CMAX, and lower Cl/F) and the altered morphine-3-glucuronide/morphine ratio in obese mice is evidence for altered morphine metabolism. Far from being definitive, our abstract and paper only “suggests” a role for leptin in altered morphine metabolism with suggestions for further study.
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