Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent

Abstract

Drug repositioning is a revolution breakthrough of drug discovery that presents outstanding privilege with already safer agents by scanning the existing candidates as therapeutic switching or repurposing for marketed drugs. Sitagliptin, vildagliptin, saxagliptin & linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin & trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight & lipophilic properties suggesting its repositioning as antiparkinsonian agent. The results of BBB crossing will be of interest for researchers interested in Parkinson's disease. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing & antimicrobial properties. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group.

Figure 1

Chemical structures of omarigliptin (a) trelagliptin (b) and the internal standard, alogliptin (c).

Figure 2

Daughter ions mass spectra in positive ESI ion detection mode with the proposed fragments showing m/z at 153.0, 134.1 & 116.1 for omarigliptin, trelagliptin & alogliptin, respectively.

Figure 3

Blank plasma (a) and blank brain homogenate (b) samples using LC-MS/MS.

Figure 4

Multiple reaction monitoring (MRM) chromatogram of omarigliptin (m/z = 399.1 to 153.0), trelagliptin (m/z = 358.2 to 134.1) and alogliptin (internal standard, m/z = 340.2 to 116.1): (a) zero plasma spiked with internal standard; (b) plasma sample spiked with the three drugs at their lower limit of quantitation (LLOQ).

Figure 5

(a) MRM chromatogram of in vivo rat plasma sample obtained 2 hours after oral administration of omarigliptin (5 mg/Kg). (b) MRM chromatogram of in vivo rat brain homogenate sample obtained 2 hours after oral administration of omarigliptin (5 mg/Kg).

Figure 6

MRM chromatograms of in vivo rats’ brain homogenate 10% samples (n = 6) obtained 2 hours after intra-nasal administration of omarigliptin (5 mg/Kg) showing concentration of 609.83 ng/g tissue ± 103.16 expressed as mean ± S.E.M (after considering the dilution factor of 10).

Figure 7

MRM chromatograms of in vivo rats’ plasma samples (n = 6) obtained 2 hours after intra-nasal administration of omarigliptin (5 mg/Kg) showing concentration of 802.35 ng/mL ± 76.85 expressed as mean ± S.E.M.

Figure 8

(a) UPLC-ESI-MS/MS chromatogram of Marizev^® tablet extract containing 2 µg/mL of omarigliptin at 1.1 min. (b) HPLC-UV chromatogram of 10 µg/mL omarigliptin in bulk at 2.1 min.

Figure 9

Effect of a single intranasal administration of OG (5 mg/kg) on brain GLP-1 level in rats. Data are presented as means ± S.E.M. (n = 6). ***p < 0.001 compared to control group (Student’s t-test).