The effect of hyperlipidemia on the pharmacokinetics, hepatic and pulmonary uptake of posaconazole in rat.

OBJECTIVES

Posaconazole (PSZ), lipophilic antifungal drug, is used for prophylactic purposes in immunocompromised patients. Our aim is to study its pharmacokinetics and tissue distribution in different elevated lipoprotein levels in rat.

METHODS

To study PSZ pharmacokinetics and protein binding, rats (n=30) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by i.p. injection of (1g/kg) poloxamer 407 in rats. Serial blood samples were collected for 72h p.o. PSZ (40mg/kg). PSZ unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits. To study tissue distribution, rats (n=64) were allocated into NL and HL groups. After p.o. administration of PSZ 40mg/kg, blood samples were collected, lungs and liver tissues were extracted over 72h.

RESULTS

Orally dosed rats showed two distinct Cmax peaks reflecting PSZ enterohepatic circulation. The incremental increase in lipoprotein levels have resulted in significant decrease in PSZ unbound fraction, a significant increase in Cmax1 and the AUC0-24h (NL=IHL<HL) and a significant decrease in PSZ terminal phase half-life (NL<IHL<HL). However, AUC0-∞ and weight normalized Cl/F were not significantly different among groups. The liver and lung PSZ uptake were decreased by hyperlipidemia resulting in lower Cmax, AUC0-8h and delayed Tmax values within those tissues. However, AUC0-72h was similar between NL and HL groups.

CONCLUSION

Poloxamer induced lipoprotein level elevation caused alterations in the PSZ pharmacokinetics and decreased its hepatic and pulmonary uptake. This raises few concerns about its activity and possible drug interactions as a prophylactic therapy in hyperlipidemic immunocompromised populations.