Toxicokinetics of the tumour cell mitochondrial toxin, PENAO, in rodents

Toxicokinetics of the tumour cell mitochondrial toxin, PENAO, in rodents.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1007/s10637-021-01065-x
Journal or Publication Title: Investigational New Drugs
Volume: 39
Number: 3
Page Range: pp. 756-763
Date: 2021
Divisions: ACRF Centenary Cancer Research Centre
Depositing User: General Admin
Identification Number: 10.1007/s10637-021-01065-x
ISSN: 0167-6997
Date Deposited: 10 Jun 2021 06:32
Abstract:

PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsonous acid) is a second-generation peptide arsenical that inactivates mitochondria in proliferating tumour cells by covalently reacting with mitochondrial inner-membrane adenine nucleotide transferase. The toxicokinetics of PENAO has been investigated in Sprague-Dawley rats to inform route of administration and dosing for human clinical trials. PENAO was well tolerated at 3.3 mg/kg daily intravenous injections but associated with significant toxicity at 10 mg/kg, primarily in the males. The major target organ for toxic effects was the kidney, with changes observed in tubular dilation, presence of casts, basophilic tubules, lymphoid aggregates and interstitial fibrosis. Kidney function was impaired in males with dose-dependent increase in serum creatinine concentration. The severity of the microscopic lesions was reduced in the females, but not the males, at the completion of the four-week recovery period. The elimination phase half-life of PENAO varied between 0.4 and 1.7 h and volume of distribution ranged from 0.25 to 0.88 L/kg for the different dose groups and treatment days, suggesting that PENAO distributes in the extracellular fluids at the doses tested. The area under the curve and clearance values indicate that male rats had reduced elimination of PENAO compared to females, which may account for the increased toxicity in males. PENAO is significantly better tolerated in rodents than its predecessor, GSAO. As GSAO was generally well tolerated with few side effects in a phase I trial in patients with solid tumours, these findings bode well for the tolerability of intravenous dosing of PENAO in patients.

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Hogg, Philip J.
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Last Modified: 10 Jun 2021 06:32
URI: https://eprints.centenary.org.au/id/eprint/1041

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