Methadone Concentrations Research Articles

The effect of fluconazole on oral methadone in dogs

ObjectiveTo determine the effects of fluconazole on oral methadone pharmacokinetics and central effects mediated by opioid receptors in dogs. Study designProspective, incomplete block. AnimalsA total of 12 healthy Beagle dogs. MethodsDogs were randomly allocated into two groups of six dogs. In total, four treatments (two treatments/group) were administered including: oral methadone (1 mg kg–1); oral fluconazole (5 mg kg–1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg–1); oral fluconazole (2.5 mg kg–1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg–1); and oral fluconazole (5 mg kg–1) every 24 hours starting 12 hours prior to oral methadone (1 mg kg–1). At least 28 days were implemented as a washout period between fluconazole treatments. Rectal temperature (RT), heart rate (HR), respiratory rate (fR), sedation scores and blood samples were obtained for 24 hours after methadone administration. Plasma drug concentrations were measured with liquid chromatography/mass spectrometry. ResultsSignificantly higher maximum plasma methadone concentration (mean, 25–46 ng mL–1) occurred in all fluconazole-administered treatments than in methadone alone (1.5 ng mL–1). The mean 12 hour methadone plasma concentration in fluconazole treatments was 11–20 ng mL–1. Significantly decreased RT and variable sedation occurred in all fluconazole treatments, but no changes occurred with methadone alone. There were no differences in HR or fR among treatments. Conclusions and clinical relevanceFluconazole significantly increases the extent and duration of oral methadone exposure in dogs resulting in significant central opioid effects.

Liver damage indices as a tool for modifying methadone maintenance treatment: a cross-sectional study

AimTo assess the effect of liver damage on methadone metabolism in opiate addicts undergoing methadone maintenance treatment (MMT).MethodsThis cross-sectional study recruited 74 patients treated at the outpatient clinic of Public Health Institute of Split-Dalmatia County from 2013-2016. Concentrations of methadone and its main inactive metabolite were measured in participants’ biological samples on regular check-ups. Urine samples obtained before oral methadone intake, and blood and urine samples obtained 90 minutes after methadone intake were analyzed using gas chromatography/mass spectrometry. Participants were divided into groups according to liver damage criteria: hepatitis C virus status (positive, negative, or clinical remission); aspartate aminotransferase to platelet ratio (APRI) index (<0.7 and ≥0.7); and fibrosis-4 score (<1.45, 1.45-3.25, >3.25).ResultsMetabolic ratio and methadone metabolite concentration in plasma decreased linearly with HCV infection status by the factor of 1.67 (P = 0.001) and 2.2 (P = 0.043), respectively. Metabolic ratio in plasma decreased in patients with APRI index ≥0.7 by the average factor of 2.12 (P = 0.01) and methadone metabolite concentration in plasma decreased by the factor of 6.16 (P = 0.009). Metabolic ratio in urine decreased with the severity of fibrosis-4 score by the average factor of 1.63 (P = 0.008), whereas methadone metabolite concentration decreased by the factor of 3.53 (P = 0.007).ConclusionLiver damage decreases methadone metabolism. Indices of liver function should be calculated regularly during MMT for methadone dose titration.

Evaluation of methadone concentrations in bitches and in umbilical cords after epidural or systemic administration for caesarean section: A randomized trial

ObjectiveTo measure plasma methadone concentrations in bitches and the umbilical cords of their puppies after systemic or epidural administration. Study designProspective, randomized, clinical study. AnimalsA total of 27 healthy pregnant female dogs undergoing caesarean section, 4.3 ± 2.3 years of age and weighing 19.9 ± 13.2 kg. MethodsThe dogs were randomly divided into three groups: 1) intramuscular methadone (0.3 mg kg–1) (group MET; n = 9); 2) epidural methadone (0.1 mg kg–1) (group METEPI; n = 9); and 3) epidural lidocaine (4.4 mg kg–1) [group CON (control group); n = 9]. Ten minutes before induction, methadone was administered intramuscularly to the group MET dogs. Anaesthesia was induced with propofol and maintained with isoflurane. Cardiovascular and respiratory parameters were monitored throughout the anaesthesia. After induction, epidural anaesthesia was administered to dogs in groups METEPI and CON. Before any treatment (T0) and, as soon as the last foetus was removed from the uterus (T1), venous blood samples were collected from each dog into heparinized tubes; the umbilical cords were collected and stored at –80 °C until pharmacological analysis was carried out. The samples were analysed using ultra performance liquid chromatography. ResultsThe cardiorespiratory parameters of the bitches and of the puppies at birth, and the Apgar scores did not differ significantly between groups. At T1 both the median maternal methadone plasma concentration and the median methadone umbilical cord concentration were higher in group MET compared to group METEPI (p = 0.0018 and p = 0.004, respectively). The maternal plasma concentration was higher than the concentration in the umbilical cords (p = 0.05) in group METEPI but not in group MET (p = 0.25). Conclusions and clinical relevanceEpidural methadone (0.1 mg kg–1) administered to bitches undergoing caesarean section is associated with lower umbilical cord methadone concentrations as compared with intramuscularly administered methadone at higher dosages (0.3 mg kg–1).

Methadone Dosage and Plasma Levels, SNPs of OPRM1 Gene and Age of First Drug Use Were Associated With Outcomes of Methadone Maintenance Treatment.

Objective: To explore the association between methadone dosage, plasma drug concentration, SNPs of μ-opioid receptor gene (OPRM1), ATP-binding cassette subfamily B member 1 gene (ABCB1), and methadone maintenance treatment (MMT) response.Method: A total of 240 Chinese Han participants receiving MMT were recruited from Shanghai. Nine single nucleotide polymorphisms (SNPs) of the OPRM1 gene and three SNPs of the ABCB1 gene were genotyped, plasma methadone concentration was detected, and a morphine urine test was taken from all subjects.Results: Methadone dosage, plasma methadone concentration, and negative rate of morphine urine test of retention participants were significantly higher, although the addiction severity index (ASI) was not significantly different between the two groups. A allele and AA genotype carriers of rs562859 (OPRM1 gene) had better compliance of MMT, and AA genotype carriers had a higher negative rate of morphine urine test. However, the difference was not significant after adjusting influence factors (age, sex, and methadone dosage). GG genotype carriers of rs3192723 (OPRM1 gene) had a significantly lower negative rate of morphine urine test, and the difference was still significant after adjusting influence factors. Logistic regression analysis showed that methadone-free trough concentration (OR = 0.910, p = 0.023) and AA genotype of rs526859 (OR = 0.580, p = 0.037) were associated with better compliance of MMT. After Bonferroni correction, only free trough concentration of methadone was negatively correlated with MMT compliance. The SNPs rs6912029 (OR = 0.021, p = 0.066) and rs6902403 (OR = 0.910, p = 0.007) of the OPRM1 gene, age at first use (OR = 1.118, p = 0.005), and average methadone dosage (OR = 1.033, p = 0.045) were associated with MMT effect. After Bonferroni correction, average methadone dosage was no longer correlated with MMT effect.Conclusion: Dosage of methadone, plasma methadone concentration, several SNPs (rs3192723, rs6912029, rs6902403) of the OPRM1 gene, and age of first drug use were associated with better MMT outcomes.

Biodegradation study of methadone by adapted activated sludge: Elimination kinetics, transformation products and ecotoxicological evaluation

The biotransformation study of difficult-to-degrade opioid analgesic methadone (MTHD) was performed by activated sludge culture adapted to high concentration of methadone (10 mg/L). The study included determination of elimination kinetics of the parent compound, taxonomic characterization of microbial culture, identification of biotransformation products (TPs) and assessment of ecotoxicological effects of biotransformation processes. The chemical analyses were performed by ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry, whereas the ecotoxicological assessment was made based on determinations of toxicity to freshwater algae. Changes of the adapted sludge culture during the experiment were followed using the 16S rRNA gene amplicon sequencing. Depending on the experimental conditions, the elimination efficiency of methadone (10 mg/L) varied from 9% to 93% with the corresponding half-lives from 11.4 days to 1.5 days. A significantly faster elimination (t1/2 from 1.5 days to 5.8 days) was achieved at cometabolic conditions, using glucose-containing media, as compared to the experiments with MTHD as a single organic carbon source (t1/2 = 11.4 days). Moreover, increased biotransformation rate following the additional supplementation of ammonia, revealed a possible importance of nitrogen availability for the transformation at cometabolic conditions. The elimination of parent compound was associated with the formation of 3 different TPs, two of which were identical to main human metabolites of MTHD, 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). EDDP represented over 90% of the total TP concentration at the end of experiment. The biodegradation of MTHD was associated with a pronounced drop in algal toxicity, confirming a rather positive ecotoxicological outcome of the achieved biotransformation processes.

The construction and application of a population physiologically based pharmacokinetic model for methadone in Beagles and Greyhounds.

Methadone is an opioid analgesic in veterinary and human medicine. To help develop appropriate pain management practices and to develop a quantitative model for predicting methadone dosimetry, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model for methadone in dogs constructed with Berkeley Madonna™ was developed. The model accounts for intravenous (IV), subcutaneous (SC), and oral administrations, and compartmentalizes the body into different components. This model was calibrated from plasma pharmacokinetic data after IV administration of methadone in Beagles and Greyhounds. The calibrated model was evaluated with independent data in both breeds of dogs. One advantage of this model is that most physiological parameter values for Greyhounds were taken directly from the original literature. The developed model simulates available pharmacokinetic data for plasma concentrations well for both breeds. After conducting regression analysis, all simulated datasets produced an R2 >0.80 when compared to the measured plasma concentrations. Comparative analysis of the dosimetry of methadone between the breeds suggested that Greyhounds had ~50% lower 24-hr area under the curve (AUC) of plasma or brain concentrations than in Beagles. Furthermore, population analysis was conducted with this study. This model can be used to predict methadone concentrations in multiple dog breeds using breed-specific parameters.

Evaluation of a new simple collection device for sampling of microparticles in exhaled breath

The microparticle fraction of exhaled breath is of interest for developing clinical biomarkers. Exhaled particles may contain non-volatile components from all parts of the airway system, formed during normal breathing. This study aimed to evaluate a new, simple sampling device, based on impaction, for collecting microparticles from exhaled breath. Performance of the new device was compared with that of the existing SensAbues membrane filter device. The analytical work used liquid chromatography-tandem mass spectrometry methods. The new device collected three subsamples and these were separately analysed from eight individuals. No difference was observed between the centre position (0.91 ng/sample) and the side positions (1.01 ng/sample) using major phosphatidylcholine (PC) 16:0/16:0 as the analyte. Exhaled breath was collected from eight patients on methadone maintenance treatment. The intra-individual variability in measured methadone concentration between the three collectors was 8.7%. In another experiment using patients on methadone maintenance treatment, the sampling efficiency was compared with an established filter device. Compared to the existing device, the efficiency of the new device was 121% greater for methadone and 1450% greater for DPPC. The data from lipid analysis also indicated that a larger fraction of the collected material was from the distal parts. Finally, a study using an optical particle counter indicated that the device preferentially collects the larger particle fraction. In conclusion, this study demonstrates the usefulness of the new device for collecting non-volatile components from exhaled breath. The performance of the device was superior to the filter device in several aspects.

Relationship between Serum Methadone Concentration and Cold Pressor Pain Sensitivity in Patients Undergoing Methadone Maintenance Therapy.

Hyperalgesia is a common clinical phenomenon among opioid dependent patients on methadone maintenance therapy (MMT) and it may be associated with undertreated pain and/or therapeutic failure. This study aimed to investigate association between serum methadone concentration (SMC) and cold pressor pain responses. Cold pressor pain responses in 147 opioid dependent patients on MMT were assessed using cold pressor test (CPT) at 0 h and at 2, 4, 8, 12, and 24 h after the dose intake. Blood samples were collected at 24 h after the dose. Serum methadone concentrations were measured using the Methadone ELISA kit and classified into two categories: < 400 ng/mL and ≥ 400 ng/mL. Eighty-eight patients (59.9%) had trough concentrations of < 400 ng/mL and 40.1% had trough concentrations of ≥ 400 ng/mL. There were significant effects of SMC on the cold pressor pain threshold (p = 0.019). Patients with concentrations < 400 ng/mL had significantly higher (almost 60% higher) cold pressor pain threshold (adjusted mean (95% CI) = 30.15 (24.29, 36.01) s) compared to those with concentrations of ≥ 400 ng/mL (18.93 (11.77, 26.08) seconds). There was also a 20% difference in pain tolerance, and 6% difference in cold pressor pain intensity score, neither of which were significant statistically (p > 0.05). Our results suggest an association of trough methadone concentration with the cold pressor pain threshold among opioid dependent patients on MMT. It would be useful to study the mechanisms underlying this association to help managing pain in such a population.

A Novel Method for Determination of Methadone in the Serum by High-Performance Liquid Chromatography with Electrochemical Detection.

In March 2013, the clinical use of oral methadone tablets was initiated in Japan. There are many factors responsible for the change in blood concentrations of methadone, and its pharmacokinetics is very complex. Therefore, a simple and accurate measurement method for methadone blood concentrations was developed using HPLC/electrochemical detector (ECD). An eluent of 10 mM Na2HPO4/CH3CN/CH3OH (20 : 19 : 3) was used as the mobile phase. The column was used the XTerra® RP18, and the voltage of the ECD was set at 400 to 800 mV. As a result, the calibration curve was linear in the ranges of 10 to 100 ng/mL (y=5012.7x+1041.1, r=0.999). The intra- and inter-day coefficients of variation were <5.2 and <5.8%, respectively. Therefore, this method was considered to be useful for the measurement of methadone blood levels in cancer patients. Also, using this method, blood methadone concentration was measured over time in a patient with cancer-associated pain who was treated with methadone. The estimated clearance (CL/F) and distribution volume (Vd/F) of methadone were 2.84 L/h and 502.8 L, respectively, and took about two weeks to reach steady state.

Comparison of the solid phase and liquid-liquid extraction methods for methadone determination in human serum and whole blood samples using gas chromatography/mass spectrometry

The aim of this study was to determine the optimal biological sample and the optimal extraction technique for monitoring methadone concentrations in biological samples. We analysed methadone in serum and whole blood samples using gas chromatography/mass spectrometry (GC/MS). Before analysis, we compared five solid-phase extraction (SPE) and two liquid-liquid extraction (LLE) methods and determined that SPE with Supelco LC-18 in serum yielded the best extraction efficiency. The limit of detection was 10 ng mL-1 and the limit of quantification 25 ng mL-1. Correlation coefficient was over 0.999 for the methadone calibration curve in linear range from 50 to 2000 ng mL-1. Intra and inter-day accuracy and precision of the method was satisfactory. The method was successfully applied for determining serum methadone in patients on maintenance therapy.

Exhaled breath condensate as an alternative sample for drug monitoring.

Exhaled breath condensate as an alternative sample for drug monitoring.

Two techniques to sample non-volatiles in breath—exemplified by methadone

The particles in exhaled breath provide a promising matrix for the monitoring of pathological processes in the airways, and also allow exposure to exogenous compounds to be to assessed. The collection is easy to perform and is non-invasive. The aim of the present study is to assess if an exogenous compound—methadone—is distributed in the lining fluid of small airways, and to compare two methods for collecting methadone in particles in exhaled breath. Exhaled particles were collected from 13 subjects receiving methadone maintenance treatment. Two different sampling methods were applied: one based on electret filtration, potentially collecting exhaled particles of all sizes, and one based on impaction, collecting particles in the size range of 0.5–7 μm, known to reflect the respiratory tract lining fluid from the small airways. The collected samples were analyzed by liquid chromatography mass spectrometry, and the impact of different breathing patterns was also investigated. The potential contribution from the oral cavity was investigated by rinsing the mouth with a codeine solution, followed by codeine analysis of the collected exhaled particles by both sampling methods. The results showed that methadone was present in all samples using both methods, but when using the method based on impaction, the concentration of methadone in exhaled breath was less than 1% of the concentration collected by the method based on filtration. Optimizing the breathing pattern to retrieve particles from small airways did not increase the amount of exhaled methadone collected by the filtration method. The contamination from codeine present in the oral cavity was only detected in samples collected by the impaction method. We conclude that methadone is distributed in the respiratory tract lining fluid of small airways. The samples collected by the filtration method most likely contained a contribution from the upper airways/oral fluid in contrast to the impaction method.

Differences in combinations and concentrations of drugs of abuse in fatal intoxication and driving under the influence cases

BackgroundIn toxicology, international classification systems focus on single intoxicants as the cause of death. It is, however, well known that very few drug related deaths are caused by a single substance and that information concerning the drug concentrations as well as the combinations of drugs are essential in order to ascertain the cause of death. The aim of the study was to assess whether those prone to fatal intoxications differ significantly from chronic drug users – in terms of demographics and drug exposure patterns. Material and methodsFatal psychoactive drug intoxications in Norway during 2012, where a forensic autopsy including toxicological analysis were performed, were included. Analytical findings in blood were compared with concentrations in blood from apprehended drivers under the influence of drugs and ethanol (DUID) during the same time period. The opioid and benzodiazepine concentrations were assessed as morphine and diazepam equivalents, respectively, in order to compare concentrations across the different groups. ResultsA total of 194 autopsy cases and 4811 DUID cases were included. Opioids were detected in around 90% of the drug intoxication cases, but in only 16% of the DUID cases. The number of substances detected in fatal intoxications was 4.9 compared to 2.6 in the DUID cases. The total opioid concentrations were significantly higher in the fatal intoxication cases compared to DUID cases (229ng/mL versus 56.9ng/mL morphine equivalents, respectively). Benzodiazepines were detected in 90% of the fatal cases. Only one fatal opioid mono-intoxication was found; a case with a very high methadone concentration (1238ng/mL). DiscussionMono-intoxication with heroin was not seen in any of the fatal intoxications in Norway, and single drug intoxications were rare (1.5%). Fatal intoxications were caused by a combination of drugs with significantly more substances as well as higher total drug concentrations among the fatal cases compared to the DUID cases. The combination of opioids and benzodiazepines seemed to represent an increased risk of death. ConclusionThe total load of drugs influence the degree of intoxication and the total concentration level must be considered, including the total number of substances. Our findings imply that international statistics regarding an opioid being the main intoxicant should have a shift in focus towards combinations of drugs (especially opioids and benzodiazepines) as a major risk factor for fatal drug overdoses.

Methadone Concentrations in Exhaled Breath Condensate, Serum and Urine of Patients Under Maintenance Treatment.

Drug abuse is a serious problem causing health, economical and psycho-social negative outcomes. Methadone is commonly used drug for management of drug addiction. Exhaled breath condensate (EBC) is a promising non-invasive biological sample which attracted more attention in recent years. This work aimed to extend the applicability of a developed preconcentration - liquid chromatographic method for analysis of methadone in serum and urine samples. Drug concentrations in EBC, serum and urine are also investigated for dose-concentration and their inter-correlations. Biological samples were collected from 53 patients receiving methadone and the concentrations were determined using a validated analytical method after a pre-concentration step. Methadone measured in all samples and there are correlations between administered dose of methadone and its serum and urine concentrations. A weak correlation is observed between dose and EBC concentration. Wider variations in EBC concentrations of methadone could be justified concerning a number of affecting parameters such as relative humidity of the collection area and further investigations are required for standardization of EBC as a non-invasive biological sample to be used in clinical practice.

Corrected QT Interval and Methadone Dose and Concentrations in Pregnant and Postpartum Women

Methadone is a standard treatment for opioid dependence in pregnancy; however, its impact on maternal corrected QT interval (QTc) has not been evaluated. We studied the association between methadone dose and enantiomer-specific plasma concentrations and QTc among pregnant and postpartum women and newborns. We assessed the relevance of QTc screening guidelines for pregnant women and infants. From 2006 to 2008, plasma methadone concentrations were measured during pregnancy, postpartum, and in cord blood in women treated for opioid dependence at a single treatment program. Electrocardiograms (ECGs) were obtained at peak methadone concentrations in mothers and within 48 hours of birth for infants. Pearson correlations were performed at each time point for QTc and R-methadone, S-methadone, and total methadone concentrations and ratio of R-methadone/S-methadone concentrations. Mean (SD) daily methadone dose for the 25 women was 94.2 (39.1) mg during pregnancy and 112.5 (46.6) mg postpartum. During the third trimester, higher methadone dose and R-methadone concentration correlated with longer QTc (Pearson r = 0.67, P < .001 and Pearson r = 0.49, P = .02, respectively), while S-methadone concentration, R-methadone/S-methadone concentration ratio, and total methadone concentration did not. Postpartum, QTc did not significantly correlate with dose or enantiomer concentrations. Infant QTc did not correlate with maternal dose at delivery or enantiomer-specific cord methadone concentrations. In pregnant and postpartum women, 13% and 17%, respectively, had QTc ≥ 450 ms, as did 19% of infants. QTc correlated with dose and R-methadone concentration during the third trimester. However, longer QTc was common among women during and after pregnancy. Given the relatively high rate of QTc > 450 ms, an ECG before and after methadone initiation is advisable for pregnant and postpartum women.

Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment.

A considerable interindividual variability in methadone pharmacokinetics is seen in patients on methadone maintenance treatment. The aim of this study was to clarify the impact of the reduced function CYP2B6*6 variant allele together with variants in other candidate genes on a steady-state methadone concentration in a naturalistic setting. Information of methadone serum concentration, dose, age, sex, and CYP2C9, CYP2C19, and CYP2D6 genotypes were collected from a routine therapeutic drug monitoring database, whereas variant alleles in CYP2B6 and CYP3A5 were retrospectively genotyped. Linear mixed model analyses were used to study the impact of gene variants on methadone serum concentration/dose (C/D) ratios, including age, sex, and time since the last dose intake as covariates. Overall, 155 serum samples from 62 patients were included in this study. The estimated mean methadone C/D ratios was 17.8 nmol·L·mg for homozygous carriers of CYP2B6*6, which was significantly (P < 0.001) higher than noncarriers (9.2 nmol·L·mg). There was no difference in C/D ratios between heterozygous carriers of CYP2B6*6 (9.1 nmol·L·mg) and noncarriers. An increase in mean methadone C/D ratios was also seen for homozygous carriers of CYP3A5*3 and heterozygous carriers of CYP2C9*2 or *3 and CYP2C19*2 or *3. Patients homozygous for CYP2B6*6 had a >90% higher methadone C/D ratio. Genotyping of CYP2B6 may therefore be of value when assessing dose requirements in methadone maintenance treatment.

Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk

ABSTRACTBackground: The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.Research design and methods: Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.Results: Thirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R2 = 0.239, p = 0.018; R2 = 0.513, p = 0.006) was shown, and it remained so if the concentration of diazepam was included (R2 = 0.347, p = 0.026, R2 = 0.513, p = 0.009).Conclusions: The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.

Increased DNA Methylation of ABCB1, CYP2D6, and OPRM1 Genes in Newborn Infants of Methadone-Maintained Opioid-Dependent Mothers

To investigate whether in utero opioid exposure, which has been linked to adverse neurodevelopmental and social outcomes, is associated with altered DNA methylation of opioid-related genes at birth. Observational cohort study of 21 healthy methadone-maintained opioid-dependent mother-infant dyads consecutively delivered at >36 weeks of gestation, and 2 comparator groups: smoking, "deprived" opioid-naïve mother-infant dyads (n = 17) and nonsmoking, "affluent" opioid-naïve mother-infant dyads (n = 15). DNA methylation of ABCB1, CYP2D6, and OPRM1 genes for mothers and babies was determined from buccal swabs. Plasma methadone concentrations were additionally measured for methadone-maintained opioid-dependent mothers. DNA methylation for ABCB1 and CYP2D6 was similar in opioid-naïve infants compared with their mothers, but was less for OPRM1 (3 ± 1.6% vs 8 ± 1%, P < .0005). Opioid-exposed newborns had similar DNA methylation to their mothers for all genes studied and greater methylation of ABCB1 (18 ± 4.8% vs 3 ± 0.5%), CYP2D6 (92 ± 1.2% vs 89 ± 2.4%), and OPRM1 (8 ± 0.3% vs 3 ± 1.6%) compared with opioid-naïve newborns (P < .0005 for all 3 genes). Infant DNA methylation was not related to birth weight, length of hospital stay, maternal smoking, dose or plasma concentration of methadone at delivery, or postcode of residence. In utero exposure to opioids is associated with increased methylation of opioid-related genes in the newborn infant. It is not clear whether these findings are due to opioid exposure per se or other associated lifestyle factors.

Silibinin affects the pharmacokinetics of methadone in rats.

The aim of the present study was to investigate the pharmacokinetic effect of silibinin on methadone in rats. Twenty-four male Sprague-Dawley rats were randomly divided into 4 groups: control group, single dose of 100mg/kg group, multiple doses of 100mg/kg group, and multiple doses of 30mg/kg group. A single dose of 6mg/kg methadone was administrated to rats orally without or with silibinin. Plasma samples were collected via tail vein at different time points and concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Compared with the control group (without silibinin), both 30 and 100mg/kg silibinin significantly increased the Cmax of methadone, but only 100mg/kg silibinin significantly increased the AUC(0-t) of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30mg/kg silibinin; its Tmax was decreased by 100mg/kg silibinin and the Cmax was increased by single dose of 100mg/kg silibinin. It is concluded that silibinin significantly altered the pharmacokinetics of methadone in rats by increasing the exposure of methadone. Further investigations in human should be conducted. Therapeutic drug monitoring of methadone in individuals undergoing methadone maintenance therapy is recommended when silibinin is concomitant.

Can Saliva and Plasma Methadone Concentrations Be Used for Enantioselective Pharmacokinetic and Pharmacodynamic Studies in Patients With Advanced Cancer?

PurposeMethadone is a potent analgesic used to treat refractory cancer pain. It is administered as a racemic mixture, with the l-enantiomer being primarily a μ-receptor agonist, whereas the d-enantiomer is an N-methyl-d-aspartate antagonist and inhibits serotonin and norepinephrine reuptake. Dose requirements vary greatly among patients to achieve optimal pain control and to avoid the risk of adverse effects. The relationship between plasma and saliva methadone enantiomer concentrations was investigated to determine if saliva could be a substitute for plasma in pharmacodynamic and pharmacokinetic studies for clinical monitoring and dose optimization of methadone in patients with advanced cancer. MethodsPatients with advanced cancer who were prescribed varying doses of oral methadone for pain management were recruited to obtain paired plasma and saliva samples. Pain scores were recorded at the time of sampling. The total and unbound plasma and saliva concentrations of the l- and d-enantiomers of methadone were quantified by using an HPLC-MS/MS method. The relationship between plasma (total and unbound) and saliva concentrations were compared. The saliva-to-plasma concentration ratio was compared versus the dose administered and the time after dosing for both enantiomers. The association of methadone concentrations with reported pain scores was compared by using a Mann-Whitney U test for significance. FindingsFifty patients receiving a mean dose of 11mg/d of methadone provided 151 paired plasma and saliva samples. The median age of the population was 61 years with an interquartile range of 53-71 years with total body weight ranging from 59-88 kg. Median (interquartile) total plasma concentrations for l- and d-methadone were 50.78 ng/mL (30.6–113.0 ng/mL) and 62.0 ng/mL (28.7–116.0 ng/mL), respectively. Median (interquartile range) saliva concentrations for l- and d-methadone were 81.5 ng/mL (28.0–203.2 ng/mL) and 44.2 (16.2–149.7 ng/mL). No relationship could be established between plasma and saliva concentrations for l- and d-methadone (r2 = 0.35 and 0.25). The saliva-to-plasma concentration analyzed with the methadone dose showed higher saliva concentrations at lower doses. Dose-normalized saliva concentrations followed a similar pattern over time compared with plasma concentrations. No correlation was found between l-methadone plasma, d-methadone plasma, l-methadone saliva, d-methadone saliva concentrations, and pain score. ImplicationsSaliva concentration was not a better predictor of pain control than plasma concentration for dose optimization and monitoring studies of methadone in patients with cancer. Although the saliva-to-plasma ratio of the concentration of methadone enantiomers was stable across the dosing range, due to the variability in individual saliva-to-plasma ratios, saliva sampling may not be a valid substitute in pharmacokinetic studies of methadone in cancer.