الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
This part contains a general introduction about the chemical names, structures, physical properties, pharmacological actions and uses of the studied drugs. It also contains literature reviews for the reported methods of analysis for the selected drugs in pharmaceutical dosage forms as well as in biological fluids. Part II This part deals with the assessment of pharmacokinetic interaction between linagliptin and tadalafil in healthy Egyptian males: A Phase IV Clinical pilot study.
This part comprises two chapters. Chapter one: This chapter presents a novel validated LC-MS method for the simultaneous determination of linagliptin and tadalafil in human plasma. Linagliptin and tadalafil along with the internal standard carvedilol were extracted from 500 𝜇L plasma using liquid-liquid extraction with ethyl acetate in the presence of 0.3 M sodium hydroxide solution. After vortexing and centrifugation, organic layer was transferred to clean tubes and evaporated in vacuo. The dried residues were reconstituted in methanol and injected into the LC-MS through a Zorbax Eclipse XDB-C18 (4.6 × 150 mm, 5 µm) column.
The mobile phase was composed of methanol: 0.05% aqueous formic acid and a gradient elution was programmed (50:50 to 90:10 over 8 minutes) at a flow rate of 1 mL/min. The injection volume was 20 µL. The instrument was operated in positive ion and selected ion recording acquisition modes. The ions utilized for quantification of linagliptin, tadalafil and carvedilol were m/z (M + H) + 473, 390 and 407, respectively. Healthy Egyptian male volunteers (𝑛 = 3), fasting >10h, were administered linagliptin tablets 5 mg/day for 13 days. Serial blood samples were collected at 0.5, 1, 1.5, 3, 4, 6, 8, 12 h post first dose, and 0.5 h before the doses 2 to 12. On day 13 the subjects were co-administered both drugs (5 mg linagliptin and 20 mg tadalafil) after > 10h fasting and serial blood samples were collected at 0.5, 1, 1.5, 3, 4, 6, 8, 12, 24, 48, 72 and 96 h after oral dosing. Plasma samples were extracted and stored at -20°C till analyzed. Linagliptin, tadalafil and carvedilol were successfully separated within 8 min. Calibration curves were linear (𝑟2 ≥ 0.999) over the range of 1–1000 ng/mL and 2–1000 ng/mL for linagliptin and tadalafil, respectively. The CV % and % Er of the mean were ≤ 20 % and limit of quantitation was 1 and 2 ng/ml for linagliptin and tadalafil, respectively. The pharmacokinetics parameters calculated for both drugs were found to be comparable to literature.
The assay was validated as per the FDA Bioanalytical Method Validation and was shown to be rapid, sensitive, and appropriate for pharmacokinetic and drugdrug interaction studies.