Prodrug of proline analogue reduces hypoxic pulmonary hypertension in rats

A polymeric prodrug of the proline analogue cis-4-hydroxy-l-proline (CHOP), poly(ethylene glycol)-lysine-CHOP or CHOP-PEG, prevents hypoxic pulmonary hypertension in rats by inhibiting collagen accumulation. A more potent prodrug was synthesized by increasing the loading of CHOP on the carrier from 14 to 100%. Pulmonary antihypertensive efficacy and pharmocokinetics are described in the rat hypoxia model. The antihypertensive effect of CHOP-PEG in rats exposed to 10% O2 for 7 d showed ∼2×102-fold greater potency than monomeric CHOP. Routes of administration were compared to determine the lowest dose of CHOP-PEG that reduced right ventricular pressure ∼50% vs. untreated hypoxic controls at 7 d. Total doses required were: continuous s.c. via an osmotic minipump, 0.8 mg; single s.c., 10 mg; single i.v., 40 mg; and single intratracheal 90 mg. Efficacy for at least 7 d postdosing in pre-established pulmonary hypertension was shown. Using an ELISA-based assay, biphasic i.v. and stable s.c. pharmacokinetic profiles were observed 72 h after single injections and 7 d after continuous s.c. infusion. Thus, this CHOP-PEG formulation prevents and reverses chronic hypoxic pulmonary hypertension in rats, is most effective when given by continuous s.c. infusion, and has favorable pharmacokinetic properties. Potent inhibitors of fibrosis appear to be promising agents in treating pulmonary hypertension and possibly other fibrosing diseases.