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. 2022 Dec:47:100477.
doi: 10.1016/j.dmpk.2022.100477. Epub 2022 Oct 13.

Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Xiao-Ming Wang  1 , Jigong Wang  2 , Valentina Fokina  1 , Svetlana Patrikeeva  1 , Erik Rytting  1 , Mahmoud S Ahmed  1 , Jun-Ho La  2 , Tatiana Nanovskaya  3
Affiliations

Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Xiao-Ming Wang et al. Drug Metab Pharmacokinet. 2022 Dec.

Abstract

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d9-methadone. The pharmacokinetic profiles of d9-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d9-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD50 value for a single intravenous dose of d9-methadone was 2.1-fold higher than that for methadone. Moreover, d9-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.

Keywords: Deuteration; Metabolism; Pharmacokinetic; Postoperative pain; d(9)-methadone.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.
Figure 1.
Chemical structures of d9-methadone and its metabolite d6-EDDP. EDDP, 2-ethylidene-1,5-dimethyl-3,3,-diphenylpyrrolidine.
Figure 2.
Figure 2.
Plasma concentration-time profiles for methadone and d9-methadone on a linear scale (A) and logarithmic scale (B) and their metabolites EDDP and d6-EDDP on a linear scale (C) and logarithmic scale (D) after intravenous administration to male CD-1 mice. Each mouse was administered 2 mg/kg of d9-methadone or methadone intravenously via the tail vein. At the predetermined time points of 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h, animals were sacrificed by CO2 asphyxiation and blood samples were obtained by cardiac puncture. The quantification of methadone, d9-methadone, EDDP and d6-EDDP in plasma samples was performed using an LC-MS/MS method. Data are presented as the mean ± s.d. of 3 separate experiments using 1 animal per time point. N=3 animals were used for each time point. EDDP, 2-ethylidene-1,5-dimethyl-3,3,-diphenylpyrrolidine.
Figure 3.
Figure 3.
Ratio of AUC0–8h of methadone or d9-methadone in different organs to the AUC0–8h in plasma. Each mouse was administered 2 mg/kg of d9-methadone or methadone intravenously via the tail vein. At predetermined time points (5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h), n=1 animal per time point was sacrificed by CO2 asphyxiation, and the tissue samples were collected. The quantification of methadone and d9-methadone in tissue samples was performed using an LC-MS/MS method. AUC values for methadone and d9-methadone in each organ were determined using Kinetica software (v. 5.1). Data are presented as the mean + s.d. of 3 separate experiments using 1 animal per time point. N=3 animals were used for each time point. AUC, area under the concentration vs. time curve. ** P < 0.01; *** P < 0.001.
Figure 4.
Figure 4.
N-demethylation of methadone and d9-methadone into their respective metabolites, EDDP (A,C) and d6-EDDP (B,D) in vitro. N-demethylation of methadone and d9-methadone into their respective metabolites, EDDP and d6-EDDP were tested in vitro using mouse liver microsomes (MLM) (A and B, respectively) and human liver microsomes (HLM) (C and D, respectively). The substrates were used in the following ranges: methadone, 7.5–100 μM with MLM and 15–300 μM with HLM; and d9-methadone, 1.875–60 μM with MLM and 7.5–100 μM with HLM. The substrates were incubates with the microsomal proteins at pH 7.4 in the presence of NADPH and in the absence of the cofactor (control reactions) at 37°C for either 10 min (MLM) or 20 min (HLM). The CYP-catalyzed formation of EDDP and d6-EDDP was calculated by subtracting the metabolite quantities determined in the control reactions from those determined in the reactions with NADPH. The rates of the formation of EDDP and d6-EDDP were dependent on the substrate concentrations and were fitted into the Michaelis-Menten model using SigmaPlot (version 14.5.0.101 for Windows, Systat Software Inc.). The insets show the corresponding Eadie-Hofstee plots. Data are presented as the mean ± s.d. from n=3 experiments, with each point in triplicate. The estimated kinetic parameters of the reactions are shown in Table 1. [V], reaction velocity, pmol/min/mg.protein; [S], substrate concentration, μM; EDDP, 2-ethylidene-1,5-dimethyl-3,3,-diphenylpyrrolidine; MLM, mouse liver microsomes; HLM, human liver microsomes.
Figure 5.
Figure 5.
The magnitude of postoperative mechanical pain hypersensitivity after intra-operative treatment with methadone or d9-methadone. Using an intra-operative regimen, we tested if d9-methadone produces greater relief of postoperative pain than methadone. Under anesthesia, immediately before plantar incision, mice received either methadone or d9-methadone (3 mg/kg, i.p.) as an intra-operative treatment. Data are presented as the mean ± s.d. of 3 experiments. N=3 animals were used for each time point. * P < 0.05; ** P < 0.01.
Figure 6.
Figure 6.
The magnitude of post-operative mechanical pain hypersensitivity after post-operative treatment. Using a post-operative regimen, we tested if d9-methadone produces greater relief of postoperative pain than methadone. After plantar incision, mice received 3 mg/kg, i.p., of either (A) methadone or (B) d9-methadone as a post-operative treatment. (C) Effect of naloxone methiodide (NLXM), a peripherally restricted opioid receptor antagonist, on the magnitude of post-operative mechanical pain hypersensitivity produced by d9-methadone. NLXM was administered postoperatively and 30 minutes prior to d9-methadone injection. NLXM completely blocked the effect of d9-methadone Data are presented as the mean ± s.d. of 3 experiments. N=3 animals were used for each time point.
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