dihydromorphine and dihydrocodeine

The Japanese Society for the Study of Xenobiotics has focused on drug development and clinical pharmacotherapy by applying cutting-edge technology and reviewing drugs. One specific area of focus has been the reverse-translational approach. This approach uses data from the investigation of clinical problems and from the detailed revisiting of preclinical studies to discover new pharmacotherapies and new methods to prevent drug-induced side effects. In 2017, the U.S. Food and Drug Administration restricted the use of prescription codeine cough-and-cold medicines in children. This decision was based on concerns about the effects of the extensive metabolite morphine in cytochrome P450 2D6 ultra-rapid metabolizers. However, there are few reports on the side effects of dihydrocodeine in Japanese children. Our laboratory measured serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression who was given dihydrocodeine phosphate in a suspected case of overdosing. Levels of dihydrocodeine and its primary metabolite, dihydromorphine, were high in this infant. However, the molar ratios of glucuronide conjugates of dihydrocodeine and dihydromorphine were lower than those found in a 3-year-old and a 6-year-old child used as references. To support and facilitate reverse-translational research, the elimination of regional differences in the methodologies used for liquid chromatography to measure drug concentrations and for the genotyping of drug-metabolizing enzymes should become the focus in hospitals, laboratories, and doctoral programs.

Topics: Child; Child, Preschool; Codeine; Cytochrome P-450 CYP2D6; Dihydromorphine; Drug Discovery; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Japan; Societies, Scientific; Translational Research, Biomedical; Xenobiotics

Aim of the study was to assess dihydrocodeine (DHC) and metabolites concentrations and their correlations with DHC analgesia in cancer patients with pain. Thirty opioid-naive patients with nociceptive pain intensity assessed by VAS (visual analogue scale) > 40 received controlled-release DHC as the first (15 patients, 7 days) or as the second opioid (15 patients, 7 days). Blood samples were taken on day 2, 4 and 7 at each study period. DHC and its metabolites were assayed by HPLC. DHC provided satisfactory analgesia when administered as the first or the second opioid superior to that of tramadol. When DHC was the first opioid administered, DHC and dihydrocodeine-6-glucuronide (DHC-6-G) concentrations increased in the second and the third comparing to the first assay. A trend of nordihydromorphine (NDHM) level fall between the first and the third assay was noted; trends of dihydromorphine (DHM) level increase in the second relative to the first determination and decrease in the third compared to the second assay were observed. When DHC followed tramadol treatment a trend of DHC concentration increase in the second relative to the first assay was noted. DHC-6-G level increased in the second and in the third comparing to the first determination; NDHM and DHM concentrations were stable. DHC and DHC-6-G concentrations increased similarly during both treatment periods which suggest their prominent role in DHC analgesia. Few significant correlations were found between DHC dose, DHC and metabolites serum concentrations with analgesia suggesting the individual DHC dose titration.

Topics: Aged; Aged, 80 and over; Analgesia; Analgesics, Opioid; Codeine; Dihydromorphine; Female; Humans; Male; Middle Aged; Neoplasms; Nociceptive Pain; Pain Management; Pain Measurement

It is not clear whether the analgesic effect following dihydrocodeine (DHC) administration is due to either DHC itself or its metabolite, dihydromorphine (DHM). We examined the relative contribution of DHC and DHM to analgesia following DHC administration in a group of healthy volunteers using a PK-PD link modelling approach.. A single oral dose of DHC (90 mg) was administered to 10 healthy volunteers in a randomised, double-blind, placebo-controlled study. A computerized cold pressor test (CPT) was used to measure analgesia. On each study day, the volunteers performed the CPT before study medication and at 1.25, 2.75, 4.25 and 5.75 h postdose. Blood samples were taken at 0.25 h (predose) and then at half hourly intervals for 5.75 h postdose. PK-PD link modelling was used to describe the relationships between DHC, DHM and analgesic effect.. Mean pain AUCs following DHC administration were significantly different to those following placebo administration (P = 0.001). Mean pain AUC changes were 91 score x s(-1) for DHC and -17 score x s(-1) for placebo (95% CI = +/- 36.5 for both treatments). The assumption of a simple linear relationship between DHC concentration and effect provided a significantly better fit than the model containing DHM as the active moiety (AIC = 4.431 vs 4.668, respectively). The more complex models did not improve the likelihood of model fits significantly.. The findings suggest that the analgesic effect following DHC ingestion is mainly attributed to the parent drug rather than its DHM metabolite. It can thus be inferred that polymorphic differences in DHC metabolism to DHM have little or no effect on the analgesic affect.

Topics: Administration, Oral; Adult; Analgesia; Analgesics, Opioid; Area Under Curve; Codeine; Cross-Over Studies; Dihydromorphine; Double-Blind Method; Female; Humans; Male; Models, Biological; Pain; Pain Measurement; Pain Threshold; Skin Physiological Phenomena

Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic and visceral pain thresholds in extensive and quinidine-induced poor metabolizers.. Eleven healthy subjects participated in a double-blind, randomized, placebo-controlled, four-way cross-over study comparing the effects of single doses of placebo and slow-release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured.. In quinidine-induced poor metabolizers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P < 0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased from 0.91% to 0.28% of the dihydrocodeine dose (P < 0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P < 0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P < 0.05).. In quinidine-induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.

Topics: Adult; Analgesics, Opioid; Codeine; Cross-Over Studies; Dihydromorphine; Double-Blind Method; Electric Stimulation; Humans; Male; Pain Measurement; Pain Threshold; Quinidine; Skin Physiological Phenomena

The opioid dihydrocodeine (DHC) is frequently used as an analgesic and antitussive agent. However, until now there have been no detailed data on dihydrocodeine metabolism in humans. We therefore investigated pathways that contribute to elimination of dihydrocodeine, and we tested the hypothesis that dihydrocodeine O-demethylation to dihydromorphine (DHM) is catalyzed by the polymorphic CYP2D6.. A single oral dose of dihydrocodeine was administered to six extensive (metabolic ratio [MR] < or = 1), two intermediate (1 < MR < 20) and six poor metabolizers (MR > or = 20) of sparteine/debrisoquin. Serum concentrations of dihydrocodeine and dihydromorphine were measured up to 25 hours, and urinary excretion of conjugated and unconjugated dihydrocodeine, dihydromorphine, and nordihydrocodeine were determined.. There were no differences in the pharmacokinetics of dihydrocodeine between extensive and poor metabolizers. However, the area under the serum concentration-time curve (AUC), partial metabolic clearance, and total urinary recovery of dihydromorphine were significantly lower in poor metabolizers (10.3 +/- 6.1 nmol.hr/L; 7.0 +/- 4.1 ml/min; 1.3% +/- 0.9% of dose) compared with extensive metabolizers (75.5 +/- 42.9 nmol.hr/L; 49.7 +/- 29.9 ml/min; 8.9% +/- 6.2%; p < 0.01). There was a strong correlation between the AUCDHC/AUCDHM ratio and the urinary metabolic ratio of sparteine (rS = 0.89, p = 0.001). No significant differences between extensive and poor metabolizers were detected in urine for conjugated dihydrocodeine (extensive metabolizers, 27.7% of dose; poor metabolizers, 31.5%), unconjugated dihydrocodeine (extensive metabolizers, 31.1%; poor metabolizers, 31.1%), conjugated nordihydrocodeine (extensive metabolizers, 6.3%; poor metabolizers, 5.4%), or unconjugated nordihydrocodeine (extensive metabolizers, 15.8%; poor metabolizers, 19.5%).. Dihydrocodeine O-demethylation to dihydromorphine is impaired in poor metabolizers of sparteine. The main urinary metabolites after administration of dihydrocodeine are the parent compound and its conjugates in extensive and poor metabolizers.

Topics: Adult; Codeine; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Dihydromorphine; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Metabolic Clearance Rate; Mixed Function Oxygenases; Phenotype; Sparteine

A ultraperformance liquid chromatography-tandem mass spectrometry method has been developed to determine dihydrocodeine (DHC) and dihydromorphine (DHM) in human plasma using dihydrocodeine-d6 and desomorphine as internal standards (IS). Acetonitrile-water-ammonium format was used as the mobile phase, in gradient elution on a C18 column. The concentration of DHC and DHM was determined in the positive ionization mode of mass spectrometry. The total chromatogram run time was 3.2 min, and the linear ranges of DHC and DHM were 1.000-400.0 ng/mL and 0.050-20.00 ng/mL, respectively. The method was fully validated concerning precision, accuracy, selectivity, linearity, recovery, stability and matrix effect. The method had been successfully applied to the bioequivalence test. In addition, we found that a high-fat diet impacts the Tmax and t1/2 of DHC.

Topics: Chromatography, High Pressure Liquid; Dihydromorphine; Humans; Reproducibility of Results; Tandem Mass Spectrometry; Therapeutic Equivalency

The levels of dihydrocodeine found in impaired individuals and in fatalities show a wide overlap in the ranges. Among other factors, the genetically controlled metabolism of dihydrocodeine should play an important role in dihydrocodeine toxicity. For the first time, the most important metabolites of dihydrocodeine were investigated in femoral blood from three fatal cases by simultaneous determination using HPLC and native fluorescence for detection. The amount of parent drug always exceeded dihydrocodeine-glucuronide formation and dihydromorphine concentrations ranged from 0.16-0.21 mg/L. The similar binding affinities of dihydromorphine and morphine to mu-opioid receptors suggest similar pharmacological effects and adverse reactions. The determination of the pharmacologically active metabolites should help to clarify the cause of death in fatal cases especially if a relatively low concentration of the parent drug is found.

Topics: Adult; Analgesics, Opioid; Chromatography, High Pressure Liquid; Codeine; Dihydromorphine; Drug Overdose; Forensic Medicine; Humans; Male; Poisoning

A report of a fatal dihydrocodeine ingestion under substitution therapy is given. Quantitation of dihydrocodeine, dihydromorphine, N-nordihydrocodeine, dihydrocodeine-6-, dihydromorphine-6- and dihydromorphine-3-glucuronide was performed simultaneously after solid-phase extraction prior to HPLC analysis, and the analytes were detected using their native fluorescence. Postmortem concentrations of blood samples from different sampling sites as well as from liver, kidney and cerebrum are reported. A hair sample was investigated to prove long-term use of the substitute drug. Site-to-site differences of the analytes from blood samples were very small. The partition behavior of the opioid glucuronides depended on the hematocrit value of the particular blood sample. Most important findings seemed that dihydromorphine and dihydromorphine-6-glucuronide concentrations decisively contributed to the toxicity of dihydrocodeine. This case report outlines that in dihydrocodeine related deaths the concentrations of the pharmacologically active metabolites should additionally be determined for reliable interpretation.

Topics: Adult; Analgesics, Opioid; Blood Chemical Analysis; Brain Chemistry; Chromatography, High Pressure Liquid; Codeine; Dihydromorphine; Fatal Outcome; Gas Chromatography-Mass Spectrometry; Hair; Humans; Kidney; Liver; Male; Morphine Derivatives; Postmortem Changes

A high-performance liquid chromatographic assay for the oxidative metabolites of dihydrocodeine, nordihydrocodeine and dihydromorphine, formed in human liver microsomal incubations, is described. A simple solvent extraction followed by reversed-phase high-performance liquid chromatography with UV detection allows quantification of both metabolites in a single assay. Standard curve concentration ranges for dihydromorphine and nordihydrocodeine were 0.05-5 and 0.2-20 microM, respectively. Assay performance was assessed by intra- and inter-day accuracy and precision of quality control (QC) samples. The difference between the calculated and the actual concentration and the relative standard deviation were less than 15% at low QC concentrations and less than 10% at medium and high QC concentrations for both analytes. The method provides good precision, accuracy and sensitivity for use in kinetic studies of the oxidative metabolism of dihydrocodeine in human liver microsomes.

Topics: Analgesics, Opioid; Animals; Antitussive Agents; Chromatography, High Pressure Liquid; Codeine; Cytochrome P-450 CYP2D6; Dihydromorphine; Humans; In Vitro Techniques; Microsomes, Liver; Oxidation-Reduction; Rats; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

The genetic polymorphism of dihydrocodeine O-demethylation in man via analysis of urinary dihydrocodeine (DHC) and dihydromorphine (DHM) by micellar electrokinetic capillary chromatography is described. Ten healthy subjects which are known to be extensive metabolizers for debrisoquine ingested 60 mg of DHC and collected their 0-12 h urines. In these samples, about 1% of the administered DHC equivalents are shown to be excreted as DHM. Premedication of 50 mg quinidine sulfate to the same subjects is demonstrated to significantly reduce (3-4 fold) the amount of O-demethylation of DHC, a metabolic step which is thereby demonstrated to co-segregate with the hydroxylation of debrisoquine. Thus, in analogy to codeine and other substrates, extensive and poor metabolizer phenotypes for DHC can be distinguished. Using the urinary DHC/DHM metabolic ratio to characterize the extent of O-demethylation, the metabolic ratio ranges of extensive and poor metabolizers in a frequency histogram are shown to partially overlap. Thus, classification of borderline values is not unequivocal and DHC should therefore not be employed for routine pharmacogenetic screening purposes. Nevertheless, the method is valuable for metabolic research and preliminary data demonstrate that the same assay could also be used to explore the metabolism of codeine.

Topics: Codeine; Dihydromorphine; Electrophoresis, Capillary; Humans; Methylation; Micelles; Phenotype; Polymorphism, Genetic; Quinidine; Reference Values

A sensitive and specific method was developed for the determination of dihydrocodeine and its metabolite dihydromorphine in human serum using codeine and morphine as internal standards. Measurement is performed with GC-tandem MS after one simple extraction step and derivatization to the pentafluoropropionic esters. Sensitivity of the method is excellent and allows for the reproducible quantification of dihydrocodeine and dihydromorphine with limits of quantification of 2 ng/ml and 40 pg/ml serum, respectively. The method is therefore well suited for investigation of the pharmacokinetics and the metabolism of dihydrocodeine.

Topics: Codeine; Dihydromorphine; Gas Chromatography-Mass Spectrometry; Humans; Morphine; Reproducibility of Results; Sensitivity and Specificity