Enhanced Extraction Technique of Omarigliptin from Human Plasma—Applied to Biological Samples from Healthy Human Volunteers

Abstract

Enhancing drug extraction from human plasma is a challenging approach that critically affects pharmacokinetic and any further clinical studies based on the drug Cmin and Cmax values. It also has a serious impact on the sensitivity and the lower limit of quantification (LLOQ) value of the bio-analytical methods. An advanced liquid chromatography tandem mass spectrometry (LC-MS/MS) bio-analytical method of omarigliptin (25–1000 nM) was established in human plasma using one-step liquid-liquid extraction. Alogliptin was used as an internal standard (IS) to attain good recovery and reproducibility while reducing the effects of the matrix. Enhanced plasma extraction of omarigliptin was successfully achieved with tertiary butyl methyl ether—diethyl ether (TBME-DEE) mixture as the extracting solvent, while using acetonitrile as the diluent solvent for the IS to effectively decrease the formed emulsion. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 399.2 to 153.0 for omarigliptin and m/z 340.2 to 116.0 for alogliptin was employed in positive Electro Spray Ionization (ESI) mode. Human plasma samples were collected after 1.5 h (tmax) of Marizev® (12.5 mg) tablets administration to healthy human volunteers showing average concentration of 292.18 nM. Validation results were all satisfactory including successful stability studies with bias below 12%. The proposed study will be valuable for ethnicity comparison studies that will be commenced on omarigliptin in Egypt by the authors in prospective study, following the FDA recommends, to evaluate possible sub-group dissimilarities that include pharmacokinetic parameters.

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

“…Although literature review showed the use of direct precipitation technique [ 16 , 17 ], the preliminary investigations in the described current research—using liquid–liquid extraction technique—showed clear enhanced results. In the previously published article [ 14 ], a mixture of diethyl ether and tertiary butyl methyl ether was used for the optimum extraction of OMR from human plasma. We tried the extraction of OMR from rats’ plasma using the same mixture [ 14 ] and it was successful because of that the rats’ plasma samples are less complicated matrix in comparison to human plasma samples but that was not the case in case of brain tissue samples.…”

“…In the previously published article [ 14 ], a mixture of diethyl ether and tertiary butyl methyl ether was used for the optimum extraction of OMR from human plasma. We tried the extraction of OMR from rats’ plasma using the same mixture [ 14 ] and it was successful because of that the rats’ plasma samples are less complicated matrix in comparison to human plasma samples but that was not the case in case of brain tissue samples. The main aim of the work was investigating OMR ratio (brain/plasma) applying the same extraction procedure to eliminate the error sources in calculations and partition coefficient.…”

“…Dipeptidyl peptidase-4 (DPP-4) inhibitors are well-known effective potential agents against type 2 diabetes mellitus (DM). OMR is a long-acting once weekly administered DPP-4 inhibitor ( Figure 1 a), that prolongs the half-life of glucagon-like peptide-1 (GLP-1) and increases the insulin production [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ] as a treatment against type 2 DM. The once-weekly OMR has the advantage of more patient compliance than the other daily-administered DPP-4 inhibitors.…”

“…Although a literature review shows that OMR pharmacokinetics factors and/or bioanalysis were studied in human [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] and rats [ 15 , 16 , 17 ] successfully according to the common FDA bioanalytical guidelines [ 30 ]. All articles considered only the plasma parameters through bio-analysis either human plasma or rats’ plasma.…”

Simultaneous Quantification of Pioglitazone and Omarigliptin in Rat Plasma by UHPLC-MS/MS and Its Application to Pharmacokinetic Study after Coadministration of the Two Drugs

“…The samples were extracted by protein precipitation. Compared with the liquid-liquid extraction methods reported in the literature to extract omarigliptin from biological samples [ 22 , 23 ], the protein precipitation was simple, cheap, and time-saving.…”