Pharmacokinetics and biodistribution of N-isopropylacrylamide copolymers for the design of pH-sensitive liposomes.

The purpose of this work was to characterize the pharmacokinetics (PK) and biodistribution of pH-responsive N-isopropylacrylamide (NIPAAm) copolymers, and to determine the impact of some physicochemical parameters on their biological profiles. Radiolabeled copolymers of NIPAAm and methacrylic acid (MAA) of different molecular weight, amphiphilicity and lower critical solution temperature (LCST) were synthesized and injected intravenously to rats. The PK and excretion profiles were monitored over 48 h. It was found that elimination occurred mainly through urinary excretion, which was principally governed by molecular weight. Above a threshold of 32,000, the polymer chains avoided glomerular filtration and presented prolonged circulation times. Moreover, the presence of alkyl moieties at the chain extremity influenced circulation time and tissue distribution of polymer chains, hypothetically through formation of micellar structures. The polymers with an LCST situated below the physiological temperature did not circulate for prolonged periods in the bloodstream and were highly captured by the organs of the mononuclear phagocyte system. Finally, the complexation of an alkylated pH-sensitive polymer with a molecular weight of 10,000 to the bilayer of PEGylated liposomes produced a drastic change in the PK parameters, indicating that the polymer remained anchored in the phospholipid bilayer in the bloodstream. These data indicate that stable pH-sensitive liposomes can be produced using excretable NIPAAm copolymers.

The effect of experimental hyperlipidemia on the stereoselective tissue distribution, lipoprotein association and microsomal metabolism of (+/-)-halofantrine.

The effect of hyperlipidemia on the biodistribution of (+/-)-halofantrine (HF) was studied in rats. Plasma, adipose, and highly perfused tissues heart, lung, liver, kidney, spleen and brain were harvested for up to 48 h after dosing animals with 2 mg/kg (+/-)-HF intravenously by tail vein. Stereospecific HPLC was used to measure HF and desbutyl-HF (DHF) enantiomer concentrations. Plasma concentrations of both HF enantiomers in hyperlipidemic (HL) exceeded those in normolipidemic (NL) rats by 11- to 15-fold. Significant increases in AUC of both HF enantiomers were noted in HL spleen tissue whereas decreases were seen in HL lung and fat. In rest of the tissues either decreases or no changes were noted in HL. The concentrations of DHF were very low in NL and HL plasma but were much higher in all highly perfused tissues. Both HF and DHF enantiomers shifted from lipoprotein deficient fraction to triglyceride-rich fractions in HL plasma following in vitro incubation of the respective racemic compounds. Compared to NL, no significant differences were noted in HF metabolism to DHF in HL liver microsomes. It would appear that both reduced plasma unbound fraction and lipoprotein associated directed uptake of lipoprotein-bound drug by tissues play roles in enantiomer biodistribution.