Journal: European journal of pharmacology

Article Title: Is there a role for biogenic amine receptors in mediating β-phenylethylamine and RO5256390-induced vascular contraction?

doi: 10.1016/j.ejphar.2024.176895

Figure Lengend Snippet: Fig. 5. The effect of 1 μM atipamezole (A-C) on medetomidine- (A), β-PEA- (B) and RO5256390-induced (C) contraction. Medetomidine CRCs were obtained (A) in the absence (● n = 5) or presence (○ n = 5) of atipamezole. β-PEA CRCs were obtained (B) in the absence (● n = 23) or presence (○ n = 5) of atipamezole. RO5256390 CRCs were obtained (C) in the absence (● n = 31) or presence (○ n = 5) of atipamezole. Contractile responses are reported as the mean percentage (±SEM) of the maximum contractile response to 60 mM KCl.

Article Snippet: (R)- (− )-phenylephrine hydrochloride (PE), serotonin hydrochloride (5-hydroxytryptamine, 5-HT), cinanserin hydrochloride, carbamoylcholine chloride (carbachol) atipamezole hydrochloride, medetomidine hydrochloride and clonidine hydrochloride were purchased from Tocris Bioscience (Abingdon, United Kingdom).

Techniques:

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Results of an in vitro screening assay to identify compounds that selectively inhibit M2 formation (but not M1 formation) from tramadol by dog liver microsomes Shown are the formation rates of M1 and M2 from tramadol in pooled DLMs incubated with each of 85 different compounds at 1 and 100 µ M inhibitor concentrations. Results are presented as the percentage of control (no inhibitor added) activity and are the average of triplicate determinations conducted in a single experiment.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: In Vitro, Screening Assay, Incubation, Activity Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Inhibitors of M1 and/or M2 formation from tramadol by pooled dog liver microsomes categorized by inhibition potency Inhibitors are listed according to whether they decrease the indicated activities by at least 50% (compared with no inhibitor added) at 1 µ M inhibitor concentration and/or also at 100 µ M inhibitor concentration. Inhibitors are also grouped by whether they inhibit M1 formation only, M2 formation only, or both M1 and M2 formation by at least 50% at that inhibitor concentration. The inhibition data used are shown in .

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Inhibition, Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: (A) Selective inhibition of the major primary (tramadol to M1 and tramadol to M2) and secondary (M1 to M5 and M2 to M5) P450-dependent metabolic pathways by fluconazole in pooled DLMs (N = 59). Shown are the rates of metabolite formation (mean ± S.D. of triplicate independent determinations) in the presence of inhibitor (0.001–1000 µM concentration) expressed as a percentage of the formation rate without inhibitor (control activity). (B) Data used to estimate the inhibition constant (Ki) for inhibition of M2 formation from tramadol by fluconazole in pooled (N = 59) DLMs. Shown are the rates of metabolite formation (mean ± S.D. of triplicate determinations) in the absence and presence of inhibitor (0.1, 1, 10, and 100 µM fluconazole), each at different substrate concentrations (5, 10, 20, 50, 100, 200, and 500 µM tramadol). The data best fit a competitive inhibition model by nonlinear regression analysis with a Ki value of 0.11 ± 0.02 µM.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Inhibition, Concentration Assay, Activity Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Plasma concentrations (nanograms per milliliter) of tramadol, M1, M2, and M5 and their respective conjugates measured 1 hour after oral administration of tramadol (5 mg/kg b.wt.) to 11 dogs (twice), and after pretreatment with fluconazole and placebo, separated by a 2-week washout period Conjugate concentrations are given as mass equivalents of the respective parent (unconjugated) compound. The data are presented as the median and the 25%–75% interquartile range of concentrations, and as the GMR and 90% confidence interval. The P value indicates the significance of paired comparisons between fluconazole and placebo treatments using the Wilcoxon signed-rank test.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Plasma concentrations (nanograms per milliliter) of tramadol (T), M1, M2, and M5 and their respective conjugates measured 4 hour after oral administration of tramadol (5 mg/kg b.wt.) to 11 dogs (twice), and after pretreatment with fluconazole and placebo, separated by a 2-week washout period Conjugate concentrations are given as mass equivalents of the respective parent (unconjugated) compound. The data are presented as the median and the 25%–75% interquartile range of concentrations, and as the GMR and 90% confidence interval. The P value indicates the significance of paired comparisons between fluconazole and placebo treatments using the Wilcoxon signed-rank test.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Urine concentrations (nanograms per milliliter) of tramadol, M1, M2, and M5 and their respective conjugates measured 4 hours after oral administration of tramadol (5 mg/kg b.wt.) to 10 dogs (twice), and after pretreatment with fluconazole and placebo separated by a 2-week washout period Conjugate concentrations are given as mass equivalents of the respective parent (unconjugated) compound. The data are presented as the median and the 25%–75% interquartile range of concentrations, and as the GMR and 90% confidence interval. The P value indicates the significance of paired comparisons between fluconazole and placebo treatments using the Wilcoxon signed-rank test.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Plasma concentrations (nanograms per milliliter) of tramadol (A), M1 (B), M2 (C), and M5 (D) measured 4 hours after oral administration of tramadol (5 mg/kg b.wt.) to 11 dogs (twice), and after pretreatment with fluconazole and placebo, separated by a 2-week washout period. Open circles are plasma concentration values for each dog measured after placebo and fluconazole pretreatments, connected by a line to show the change that occurred within individual subjects. Also shown are P values obtained using the Wilcoxon signed-rank test comparing fluconazole to placebo pretreatments.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Urine concentrations (nanograms per milliliter) of tramadol (A), M1 (B), M2 (C), and M5 (D) measured 4 hours after oral administration of tramadol (5 mg/kg b.wt.) to 10 dogs (twice), and after pretreatment with fluconazole and placebo, separated by a 2-week washout period. Note that a urine sample could not be obtained from dog 11 after placebo pretreatment. Open circles are urine concentration values for each dog measured after placebo and fluconazole pretreatments, connected by a line to show the change that occurred within individual subjects. Also shown are P values obtained using the Wilcoxon signed-rank test comparing fluconazole to placebo pretreatments.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques: Concentration Assay

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Relative proportions of tramadol, M1, M2, and M5 (unconjugated plus conjugated) measured in urine samples 4 hours after oral administration of tramadol (5 mg/kg b.wt.) to 10 dogs (twice), and after pretreatment with placebo (A) and fluconazole (B), separated by a 2-week washout period. Each stacked bar show values for individual dogs expressed as a molar percentage of total measured compounds for that urine sample.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques:

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Urine conjugated/unconjugated molar ratios of tramadol, M1, M2, and M5 measured 4 hours after administration of tramadol (5 mg/kg b.wt.) orally to 10 dogs (twice), and after pretreatment with fluconazole and placebo, separated by a 2-week washout period The data are presented as the median and the 25%–75% interquartile range of concentrations. The P value indicates the significance of paired comparisons between fluconazole and placebo treatments using the Wilcoxon signed-rank test.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques:

Journal: Drug Metabolism and Disposition

Article Title: Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs

doi: 10.1124/dmd.118.083444

Figure Lengend Snippet: Effect of fluconazole on tramadol metabolism in dogs based on the results of this study. The primary pathway for tramadol metabolism is N-demethylation to M2 followed by O-demethylation to M5. M2 and M5 (and their phase 2 metabolism conjugates) are the most abundant metabolites found in dog plasma and urine. O-demethylation of tramadol to M1 followed by N-demethylation to M5 is a minor pathway, and only low concentrations of M1 and its conjugates are detected in plasma and urine. Fluconazole was identified as a potent inhibitor of M2 formation from tramadol and M5 formation from M1 in DLMs without inhibiting the other two pathways. Oral pretreatment of dogs with fluconazole markedly increased plasma and urine concentrations of tramadol and M1 and decreased M2 and M5 concentrations.

Article Snippet: NADP + , isocitrate dehydrogenase, DL-isocitrate, and fluconazole were obtained from Sigma-Aldrich (St. Louis, MO). (+)-Tramadol hydrochloride, (−)-tramadol, O- desmethyltramadol hydrochloride, O- desmethyltramadol-D 6 , N- desmethyltramadol, N- desmethyltramadol-D 3 hydrochloride, and N , O- didesmethyl tramadol-d3 hydrochloride were purchased from Toronto Research Chemicals Inc. (Toronto, Ontario, Canada).

Techniques:

Journal: Micromachines

Article Title: Highly Sensitive Label-Free Detection of Small Molecules with an Optofluidic Microbubble Resonator

doi: 10.3390/mi9060274

Figure Lengend Snippet: Real-time binding curves of small molecules ( a ) medetomidine HCl; ( b ) cetrimonium bromide; ( c ) reboxetine mesylate with surface-immobilized streptavidin on packaged OFMBR sensor at respective concentration of 205 pM (Insets show enlarged views of the binding curves); ( d ) Binding curves of surface-immobilized streptavidin with flowing magnolol at concentrations of 100 pM, 500 pM, and 1000 pM. Vertical lines are the starts of association and dissociation phases.

Article Snippet: Magnolol, medetomidine HCl, cetrimonium bromide, and reboxetine mesylat were from Selleck (Houston, TX, USA).

Techniques: Binding Assay, Concentration Assay