Electronic Theses and Dissertations

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Browsing Electronic Theses and Dissertations by Author "Ahmed, Mahmoud S"

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    Pharmacokinetics of Bupropion and its Pharmacologically Active Metabolites in Pregnancy
    Fokina, Valentina Mikhaylovna; Ahmed, Mahmoud S; Nanovskaya, Tatiana N; Abdel-Rahman, Sherif Z; Rytting, Erik; Snodgrass, Wayne R; Abdel-Rahman, Susan M
    Bupropion, an antidepressant and anti-smoking medication, is used for treatment of depression during pregnancy, however its efficacy as a smoking cessation aid in pregnancy has not been confirmed. The drug is extensively biotransformed by liver with the formation of pharmacologically active metabolites, namely hydroxybupropion (OHBUP), threo- (TB) and erythrohydrobupropion (EB). CYP2B6 is the primary enzyme catalyzing the formation of OHBUP; the latter is the main plasma metabolite of bupropion and is thought to contribute majorly to pharmacological efficacy of the drug. CYP2C19 enzyme is involved in hydroxylation of bupropion, as well as TB and EB. Pregnancy-associated changes in maternal physiology may alter the pharmacokinetics of bupropion and thus influence the efficacy of bupropion in promoting cessation in pregnant smokers. Therefore, the primary objective of this study was to evaluate the effect of pregnancy on bupropion biodisposition. In addition, we studied the impact of functional genetic variants of CYP2B6 and CYP2C19 on bupropion pharmacokinetics in pregnancy. Our data indicated that the isoform-specific effect of pregnancy on bupropion-metabolizing enzymes and changes in renal function during pregnancy could collectively result in slight increase of bupropion apparent oral clearance; however, no changes in the plasma levels of OHBUP were evident. Further, our data demonstrated that the effect of CYP2B6*6 (reduced function allele) and CYP2C19*2 (loss-of-function allele) on bupropion biodisposition in pregnancy are similar to those observed in the non-pregnant state. We also investigated the in vivo placental transfer of the drug and its metabolites. For this purpose, the drug and its metabolites were determined in the matching maternal-umbilical cord blood plasma samples collected at delivery from pregnant women treated with bupropion for depression during pregnancy. The levels of OHBUP, TB, and, with a few exceptions, bupropion, in the umbilical cord venous plasma were lower than those in the matching maternal plasma, suggesting limited fetal exposure. In addition, we found that the concentrations of OHBUP and TB in the fetal circulation could be predicted from those in the maternal plasma. Further, bupropion and its metabolites were determined in the amniotic fluid, suggesting additional pathway of fetal exposure to maternally administered bupropion.
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    Synthesis towards Salvinorin Scaffold to Develop a Potential Pain Therapeutic and Selective, Potent Kappa Opioid Ligands
    Strong, Tori 1977-; Gilbertson, Scott R; Westlund-High, Karin; Cunningham, Kathryn A; Gallagher, Joel P; Ahmed, Mahmoud S
    Effective chronic pain management has posed a challenge for patients who have sought after traditional therapy, opioid analgesics. Particularly in patients with chronic pancreatitis, traditional therapy has failed to assist with pain management causing daily activity to be an even bigger challenge. Drugs like morphine or codeine, mu opioid agonists, have been utilized for pain management although these agonists have non-selective, opioid receptor subtype activity and side effects that ensue with chronic use that include constipation, addiction and respiratory depression. With the pancreas having a high density of kappa opioid receptors, a kappa subtype selective agonist could serve as a target molecule to develop as a pain therapeutic for patients with chronic pancreatitis. Where most alkaloids isolated over the years share characteristics like being plant derived, having similar structural functionalities and having cross affinity to opioid receptor subtypes, Salvinorin A has emerged as a very unique alkaloid. Salvinorin A is a non-nitrogenous alkaloid that selectively binds to the kappa opioid receptor subtype, implicating it as a potential target for development as a pain therapeutic for chronic pancreatitis as well as a scaffold for selective kappa opioid ligands. Synthesis of the Salvinorin scaffold is the basis of this body of work to not only build on the profile established in previous work but characterize through modifications that only synthesis can provide. This dissertation describes the synthesis of the key molecule as the pivotal molecule for generating analogues for the Salvinorin scaffold. Likewise, this work demonstrates the nociception response of Salvinorin A in the persistent pancreatitis model. Salvinorin A serves as a unique target for development both chemically and biologically; and this work establishes the foundation to bridge the gap between the two.