Could interspecies differences in the protein binding of flavone acetic acid contribute to the failure to predict lack of efficacy in patients?
- 29 Downloads
We investigated the differences in plasma protein binding of flavone acetic acid (FAA) in mice and men in an attempt to explain the inter-species differences in response. In vitro data indicate both qualitative and quantitative differences in FAA protein binding: approximately 80% is bound in humans, with two different types of binding site identified; in mice, 70% is bound and only one binding site could be described. Protein binding is dose-dependent in both species. Plasma samples from 20 patients receiving FAA showed that most achieved levels that would be active in mice. We conclude that these differences in protein binding are insufficient to explain totally the observed differences in response.
KeywordsAcetic Acetic Acid Cancer Research Plasma Sample Plasma Protein
Unable to display preview. Download preview PDF.
- 1.Belforte G, Bona B, Milanese M (1984) Advanced modeling and identification techniques for metabolic processes. CRC Crit Rev Biomed Eng 10(4): 275Google Scholar
- 2.Bibby MC, Double JA, Phillips RM, Loadman PM (1987) Factors involved in the anti-cancer activity of the investigational agents LM985 (flavone acetic acid ester) and LM975 (flavone acetic acid). Br J Cancer 55: 159Google Scholar
- 3.Corbett TH, Bissery MC, Wozniak A, Plowman J, Polin L, Tapazoglou E, Dieckman J, Valeriote F (1986) Activity of flavone acetic acid (NSC-347512) against solid tumours of mice. Invest New Drugs 4: 207Google Scholar
- 4.Kerr DJ, Kaye SB, Cassidy J, Bradley C, Rankin EM, Adams L, Setanoians A, Young T, Forrest G, Soukop M, Clavel M (1987) A phase I and pharmacokinetic study of flavone acetic acid. Cancer Res 47: 6776Google Scholar
- 5.Plowman J, Narayanan V, Dykes D, Szarvasi E, Briet P, Yoder OC, Paull K (1986) Flavone acetic acid (NSC-347512), a novel agent with preclinical antitumour activity against colon adenocarcinoma 38 in mice. Cancer Treat Rep 70: 631Google Scholar
- 6.Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51: 660Google Scholar
- 7.Zaharko DS, McCormack JJ (1987) A binding isotherm useful for predicting free drug in-vivo. Pharmacologist 29(3): 74Google Scholar
- 8.Zaharko DS, Grieshaber CK, Plowman J, Craddock JC (1986) Therapeutic and pharmacokinetic relationships of flavone acetic acid: an agent with activity against solid tumours. Cancer Treat Rep 70(12): 1415Google Scholar