Pharmacokinetics, metabolism, tissue and tumour distribution of the neuropeptide growth factor antagonist [Arg6, D-Trp7,9, NmePhe8]-substance P (6—11) in nude mice bearing the H69 small-cell lung cancer xenograft

Abstract

[Arg6, D-Trp7,9, NmePhe8]-Substance P (6-11) (codenamed antagonist G) represents the first board spectrum antagonist of a number of neuropeptides shown to act as growth factors in small-cell lung cancer (SCLC) and is shortly to enter clinical trials. Pharmacokinetics, metabolism, tissue disposition have been studied in mice (nu/nu) bearing the NCI-H69 human SCLC xenograft after systemic drug adminstration at an active dose (45 mg/kg i.p.). The peptide exhibited relatively long half life (28.9 min; clearance 45.6 ml/min/kg) and distributed widely (volume of distribution 1490 ml/kg). Marked accumulation of antagonist G (and its metabolites) was noted in the liver (AUC5278 micrograms/g x min) and to a lesser extent the spleen (AUC 930 micrograms/g x min) but only low levels appeared to cross the blood brain barrier (AUC in brain, 20 micrograms/g x min) or be taken up into the heart (AUC 101 micrograms/g x min). Tumour uptake was intermediate in value out of the 7 tissues studied (AUC 195 micrograms/g x min). Metabolism was restricted almost exclusively to the C terminal of the peptide producing 4 major products: M1, deamidated antagonist G; M2, Harg-DTrp-NmePhe-DTrp-Leu-OH, both of which retain growth factor antagonist activity; M3, a combination of oxidised antagonist G [Met11(O)] and oxidised deamidated antagoinst G; and M4, a combination of H-Arg-DTrp-NmePhe-DTrp-OH and H-DTrp-NmePhe-DTrp-Leu-OH. Extensive biotransformation to predominately M1 and M2 occurred in most tissues including the tumour where the parent peptide accounted for only 48.5% of the total. Levels of antagonist G required to produce a small but significant effect on the growth of SCLC cell lines in vitro are in the region of 4-7 microM. Taking into account metabolites, a peak concentration of 4.1 microgram/g (4.3 microM) was achieved in the H69 xenograft. These studies reveal a favourable preclinical pharmacology profile for antagonist G and offer hope that anticancer activity may be achievable in man.