The Preclinical Pharmacokinetics and Metabolism of Peloruside A

Abstract

Peloruside A (PelA) is a novel microtubule-targeting anticancer agent with a similar mechanism of action to that of the taxanes. It has shown potency against a wide range of cancer cells in vitro, and promisingly against those cells which are otherwise resistant to the classical microtubule targeting agents. More recently it has shown to inhibit tumour growth in tumour xenograft mice models. In vitro models have also shown that PelA has therapeutic potential in neurodegenerative diseases. Although the pharmacodynamics of peloruside A are well known, next to nothing is known about its pharmacokinetics, including its distribution to the tumour and the brain. This study aimed to investigate the preclinical pharmacokinetics of peloruside A in plasma and tissues and its metabolism in liver microsomes. NIH-III mice with NCI-H460 tumours were dosed either intravenously with 2 mg/kg of PelA or orally with 10 mg/kg and plasma, liver, kidney, tumour, and brain were collected at time points between 5 minutes to 24 hours after dosing. The concentration of PelA in plasma and the tissues was determined using a triple quadrupole mass spectrometer (LC-MS/MS) and pharmacokinetic parameters were estimated by non-compartmental analysis. Metabolism of PelA was determined in CD1 mouse and human liver microsomes (MLM and HLM) incubated with PelA for 60 min with NADPH, with metabolites identified by mass spectra scans conducted on the LC-MS/MS at an m/z range of 100-1000. PelA was rapidly absorbed with an oral bioavailability of 45%, and quickly distributed from the plasma compartment rapidly to the liver and kidney. It was also shown to distribute into the tumour at concentrations in excess of those that have shown anti-cancer effects in vitro and to accumulate in the tumour over a long time. In contrast PelA is unable to penetrate into the brain at any relevant levels, meaning that it is not suitable for the treatment of neurodegenerative diseases. In the metabolite studies, PelA signals decreased in both MLM and HLM, with 6 potential metabolites of unknown chemical structure being identified in MLM but no obvious metabolites were observed in HLM. While it was suggested from microsomes that there is a large degree of hepatic metabolism, the pharmacokinetic studies have shown that sufficient levels of PelA can still reach the systemic circuit even when dosed orally. These results show that PelA has suitable bioavailability for oral dosing, and accumulates in the tissue site of interest. PelA has potential as a candidate for cancer chemotherapy, and these results support the further development of this compound with more research required to characterise the metabolites of PelA.