The influence of hyperlipidemia on the pharmacodynamic and pharmacokinetic aspects of lipophilic drugs was explored. The antiarrhythmic, amiodarone, and the antifungal, ()-ketoconazole, were used as model drugs. Experimental hyperlipidemia was induced in rat using poloxamer 407 and two sensitive novel HPLC assays were developed.
In a multiple dosing study, hyperlipidemia increased amiodarone plasma concentrations, heart concentrations and electrocardiographic changes. The amiodarone heart uptake could not be totally attributed to its unbound fraction, where the cardiac very low density lipoprotein receptors seemed to play a role in the uptake of bound drug.
Amiodarone liver metabolism in presence and absence of hyperlipidemia was studied using isolated primary rat liver hepatocytes. The metabolism of amiodarone was lower in hepatocytes isolated from hyperlipidemic than those from normolipidemic rats. Hyperlipidemic serum resulted in a decrease in amiodarone metabolism and when coincubated, the expected decrease in unbound fraction seemed to resulted in greater inhibition of metabolism.
()-Ketoconazole showed stereoselectivity in its pharmacokinetics in rat with (+)-ketoconazole showing higher plasma concentrations than its antipode. This was attributed to its higher protein binding. There was no difference in the total bioavailability of the two enantiomers. Ketoconazole enantiomers exhibited nonlinear pharmacokinetics. In normolipidemic rat plasma ketoconazole enantiomers were more than 95% bound to lipoprotein deficient fraction. Hyperlipidemia resulted in shifting both enantiomers 20% to very low density and low density lipoprotein fractions.
In a pharmacokinetic assessment, hyperlipidemia was found to increase ketoconazole enantiomer volume of distribution. Moreover, the stereoselectivity ratios of most pharmacokinetic parameters were changed. After oral dosing, the uptake of (-)-ketoconazole was significantly decreased. Since ketoconazole is used as a potent CYP3A inhibitor, alteration in liver concentrations of (-)-ketoconazole, the more potent inhibitory enantiomer, could decrease its CYP inhibitory potential.
Hyperlipidemia potentiated the CYP-mediated interaction between ketoconazole and midazolam with significantly higher midazolam AUC and lower clearance. This was attributed to the inhibitory action of ketoconazole and the effect of hyperlipidemia on the binding of midazolam. Hyperlipidemia was found to unexpectedly decrease midazolam unbound fraction in plasma.
In conclusion, the findings could explain some unexpected dose versus effect outcomes in hyperlipidemic patients receiving amiodarone or ketoconazole. / Pharmaceutical Sciences
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1465 |
| Date | 11 1900 |
| Creators | El Sayed, Dalia |
| Contributors | Dr. Brocks, Dion R (Faculty of Pharmacy and Pharmaceutical Sciences, Dr. Brocks,Dion R. (Faculty of Pharmacy and Pharmaceutical Sciences), Dr. Jamali, Fakhreddin (Faculty of Pharmacy and Pharmaceutical Sciences), Dr. El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences), Dr. Jurasz, Paul (Faculty of Pharmacy and Pharmaceutical Sciences), Dr. Baker, Glen (Department of Psychiatry), Dr. Marleau, Sylvie (Faculty of Pharmacy, University of Montreal) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 2065445 bytes, application/pdf |
| Relation | Hamdy, DA (2010). http://www.ncbi.nlm.nih.gov/pubmed/20537491, Hamdy, DA (2009). http://www.ncbi.nlm.nih.gov/pubmed/20332028, Hamdy, DA (2009). http://www.ncbi.nlm.nih.gov/pubmed/18988259, Hamdy, DA (2008). http://www.ncbi.nlm.nih.gov/pubmed/18205135 |
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