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

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Abstract
[Arg6, D-Trp7-9, NmePhe8)-Substance P (6–11) (codenamed antagonist G) represents the first broad 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 and tumour disposition have been studied in mice (nu/nu) bearing the NCI-H69 human SCLC xenograft after systemic drug administration at an active dose (45 mg/kg i.p.). The peptide exhibited a 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 (AUC 5278 μg/g × min) and to a lesser extent the spleen (AUC 930 μg/g × min) but only low levels appeared to cross the blood brain barrier (AUC in brain, 20 μg/g × min) or be taken up into the heart (AUC 101 ng/g × min). Tumour uptake was intermediate in value out of the 7 tissues studied (AUC 195 (μg/g × min). Metabolism was restricted almost exclusively to the C terminal of the peptide producing 4 major products: M1, deamidated antagonist G; M2, H-Arg-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 antagonist G; and M4, a combination of H-Arg-DTrp-NmePhe-DTrp-OH and H-DTrp-NmePhe-DTrp-Leu-OH. Extensive bio-transformation to predominately Ml 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 μM. Taking into account metabolites, a peak concentration of 4.1 μg/g (4.3 uM) 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.