In the past, hyperlipidemia (HL) has been shown to affect the pharmacokinetic and pharmacodynamic properties of lipophilic drugs extensively bound to lipoproteins, including halofantrine (HF). The present thesis examined the effect of HL on the biodistribution, metabolism and electrocardiographic (ECG) effects of HF in the poloxamer 407 rat model of HL. The HL state caused unexpected changes in the distribution of HF enantiomers. In contrast to plasma, concentrations of desbutyl-HF (DHF) were much higher in highly perfused tissues. Following in vitro incubation of racemic HF and DHF, HF and DHF enantiomers shifted from the lipoprotein deficient fraction to triglyceride-rich fractions in HL plasma. No significant differences were noted in HF metabolism between NL and HL liver microsomes. It appears that both reduced plasma unbound fraction and lipoprotein associated directed uptake of lipoprotein-bound drug by tissues play roles in enantiomer biodistribution. In everted gut metabolism, formation of DHF enantiomers was inversely proportional to bile concentration whereas addition of lipids in the presence of bile caused a significant decrease in DHF:HF ratio of (-)-enantiomers. Pre-treatment of rats with peanut oil had no significant effect on DHF formation in the incubated sacs or microsomal preparations, nor did it affect the expression of intestinal CYP450. The above results were consistent with previous in vivo evaluations showing that the DHF to HF ratio was decreased by the ingestion of a high fat meal. In the ECG study, HL by itself had no effect on the ECG. In HL rats, plasma but not heart concentrations of the HF enantiomers were significantly higher compared to NL rats. DHF did not impart significant ECG prolonging effects after HF administration. The unbound fraction of HF was the controlling factor for drug uptake by the heart. Despite the lack of difference in HF heart concentrations, the QT and QTc intervals were significantly higher in HL compared to NL rats, suggesting a greater vulnerability towards HF induced QT interval prolongation in the HL state. The HL serum resulted in decreased metabolism of HF enantiomers in the isolated primary rat hepatocytes. Studies with LLC PK1 and NRK 52E cells showed that HF is not a substrate of P-glycoprotein transporters. / Pharmaceutical Sciences

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