Pharmaceutical characterization of selected xenobiotics utilizing novel drug delivery systems
| dc.contributor.author | Alrushaid, Samaa | |
| dc.contributor.examiningcommittee | Davies, Neal (Pharmacy) Sayre, Casey (Pharmacy) Miller, Donald (Pharmacology and Therapeutics) Kwon, Glen S. (University of Wisconsin-Madison) | en_US |
| dc.contributor.supervisor | Burczynski, Frank (Pharmacy) | en_US |
| dc.date.accessioned | 2018-04-27T18:05:07Z | |
| dc.date.available | 2018-04-27T18:05:07Z | |
| dc.date.issued | 2017-08 | en_US |
| dc.date.issued | 2017-09 | en_US |
| dc.date.issued | 2018-01 | en_US |
| dc.date.submitted | 2018-04-23T21:46:02Z | en |
| dc.degree.discipline | Pharmacy | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Drug development is a very costly procedure. Many failed clinical trials could be prevented by optimizing drug formulations or delivery systems of an existing drug, which may be a better and less costly approach over developing a new compound. In this thesis, chemical structure modification was employed as a drug delivery optimization strategy to improve the efficacy and safety of selected xenobiotics, and examine their biodistribution and feasibility for further drug development using in silico, in vitro, and in vivo studies. DoxQ, a derivative of the anticancer drug doxorubicin, was developed to mitigate poor bioavailability and systemic toxicities associated with doxorubicin. The speculated mechanism of cardiac and renal toxicities induced by doxorubicin involves oxidative stress while the mechanism behind the poor bioavailability is due to doxorubicin being a substrate of a major metabolic enzyme CYP3A4 and P-glycoprotein efflux transporter. To mitigate these effects, the flavonoid quercetin was conjugated to doxorubicin (DoxQ) as it is a potent antioxidant and exhibits inhibitory effects on CYP3A4 and P-glycoprotein, and also is absorbed via intestinal lymphatics. DoxQ changed the physiochemical properties of the parent compound doxorubicin as predicted in silico by computer software packages. In vitro DoxQ inhibited CYP3A4, showed higher cellular uptake by MDCK-MDR cells than doxorubicin, was less toxic to cardiomyocytes, and reduced the expression of cardiac toxicity and oxidative stress markers. DoxQ administered intravenously to rats had a short half-life, was primarily eliminated via non-renal routes, less nephrotoxic than doxorubicin and did not show significantly higher cardiac toxicity than doxorubicin. Oral administration of DoxQ increased the systemic exposure of doxorubicin by ~1.5 fold compared to oral doxorubicin, and showed that Dox was partially absorbed via intestinal lymphatics. MyoNovin® is a novel skeletal muscle regenerator designed to treat muscle atrophy. In silico modelling suggests that MyoNovin® is a potentially good candidate for oral or transdermal administration. In vitro MyoNovin® was not cardiotoxic < 8 μM and did not inhibit CYP3A4. A single intravenous dose of MyoNovin® to rats showed that it has a short half-life, distributes to tissues, and shows no evidence of renal or cardiac toxicity. | en_US |
| dc.description.note | October 2018 | en_US |
| dc.identifier.citation | Alrushaid S, Zhao Y, Sayre CL, Maayah ZH, Forrest ML, Senadheera SN, Chaboyer K, Anderson HD, El-Kadi A, Davies NM . Mechanistically Elucidating the In-Vitro Safety and Efficacy of a Novel Doxorubicin Derivative. Drug Deliv Transl Res. 2017;7(4):582-97. | en_US |
| dc.identifier.citation | Alrushaid S, Sayre CL, Yáñez JA, Forrest ML, Senadheera SN, Burczynski FJ, Löbenberg R, Davies NM. Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative. Pharmaceutics. 2017;9(3):35. | en_US |
| dc.identifier.citation | Alrushaid S, Davies NM, Anderson JE, Le T, Yáñez JA, Maayah ZH, El-Kadi AOS, Rachid O, Sayre CL, Löbenberg R, Burczynski FJ. Pharmaceutical Characterization of MyoNovin®, a Novel Skeletal Muscle Regenerator: in silico, in vitro, in vivo Studies. J Pharm Pharm Sci. 2018;21(1s):1-18. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/33007 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Drug Delivery and Translational Research | en_US |
| dc.publisher | Pharmaceutics | en_US |
| dc.publisher | The Journal of Pharmacy and Pharmaceutical Sciences (JPPS) | en_US |
| dc.rights | open access | en_US |
| dc.subject | Drug delivery | en_US |
| dc.subject | Pharmacokinetics | en_US |
| dc.subject | DoxQ | en_US |
| dc.subject | Lymphatics | en_US |
| dc.subject | Bioavailibility | en_US |
| dc.subject | Cancer | en_US |
| dc.subject | MyoNovin | en_US |
| dc.subject | Skeletal muscle | en_US |
| dc.subject | nitric oxide | en_US |
| dc.subject | toxicity | en_US |
| dc.title | Pharmaceutical characterization of selected xenobiotics utilizing novel drug delivery systems | en_US |
| dc.type | doctoral thesis | en_US |