تصنيع ودراسة مواصفات وحركية الدواء المخبرية لطلائع الغابابنتين.

الموضوعات

طب

الملخص

iiiAbstractGabapentin has non-linear pharmacokinetics which limitits clinical effectiveness. The absorption of gabapentin occurs by L-amino acid transport system through a low-capacity nutrient transporter expressed in a narrow part of the upper small intestine. This is a carrier-mediated and saturable transport systemleading to dose-dependent pharmacokineticsof gabapentin-as the dose increases, the bioavailability decreases.Based on Kirby`s enzyme model, three gabapentin prodrugs were proposed. They are expected to have higher and predictable bioavailability, in contrast to gabapentin, as a result of improving passive absorption. Moreover, the proposed prodrugs can be used in different dosage forms due to their potential solubility in organic and aqueous media. The prodrugs were synthesized andcharacterized bymelting point,fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopyand liquid chromatography-mass spectrometry analytical techniques to guarantee pure gabapentin prodrugs. Hydrolysis of gabapentin prodrugs was investigated using high-performance liquid chromatography at constant temperature (37oC) using differentbuffer pHs, namely, 0.1N HCl, pH 3, pH 6.8and pH 7.4 to resemble the physiological environments in the human body. Furthermore, in silico predictionof physiochemical parameters, absorption, distribution, metabolism, excretion, toxicity, and blood-brain barrier permeability for the three synthesized gabapentin prodrugs were studied. Gabapentin prodrug 1experimental half-life values in 0.1N HCl, buffer pH‘s3, 6.8 and 7.4 were 16.57, 17.76, 101.91, and 119.48 hours, respectively. Gabapentin prodrug2 was hydrolyzed into its parent drug in 0.1N HCl, buffer pH‘s 3, 6.8, and 7.4 with experimental half-life values of 20.3, 22.70, 130.75 and 277.2 hours, respectively. However, gabapentin prodrug 3 was extremely insoluble in acidic environment and completely stable at pH 6.8 and pH 7.4. Thein silicoresults revealedthat all the synthesized gabapentin prodrugs comply with Lipinski‘s rule of five, have good and favorable pharmacokinetic properties, have positive central nervous system permeability, and none of the prodrugs had high risk of toxicity. Three gabapentin prodrugswere synthesized and characterizedand theirin vitrointraconversion to their parent drugs showed that half-life was primarily affected by the pH of the medium, the distance between the two reactive centers,and the pka of the linker.In vivopharmacokinetic studies will be done for both gabapentin prodrug 1-2 in order to determine the bioavailability and the duration of action of the tested prodrugs.

روابط وملفات

التعريف والنوع

رقم الوثيقة

fef0477d-5510-48a7-9cbb-76768d8bc951

رقم العقد

0

نوع الوسائط

Crawler

نوع المحتوى

الرسائل العلمية

صيغة المصدر

رسائل ماجيستير

نوع الملف

pdf text

أسماء الملفات

1696579_1.pdf

بيانات النشر

ترجمة العنوان

Synthesis, Characterization and In Vitro Kinetic Study of Gabapentin Prodrugs

ألقاب المؤلفين

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اللغة

English

المصدر والدورية

اسم المصدر

تصنيع ودراسة مواصفات وحركية الدواء المخبرية لطلائع الغابابنتين.

المحتوى والصفحات

عدد الصفحات

0

إشراف وإعداد

الإشراف

رفيق قرمان

الإعداد

فاطمة عصام عبد القادر حداد

الاقتباسات الببليوغرافية