Unique pharmacology of KAR-2, a potential anti-cancer agent: absorption modelling and selective mitotic spindle targeting.
Bis-indols are a large group of the anti-cancer agents, which effectively arrest the uncontrolled division of the cancerous cells. Their use in clinical chemotherapy is still limited because of: (i) the non-specific targeting of the mitotic cells; (ii) low bioavailability of the drugs. KAR-2 has been identified as a tubulin binding agent which displays significantly lower cytotoxicity but favourable anti-cancer potency than its mother molecule, vinblastine. The objective of this paper, on one hand, was to show that the human intestinal epithelial Caco-2 cells, used for pharmacokinetic studies display distinct sensitivity against KAR-2 and vinblastine due to their distinct targeting of mitotic and interphase microtubular systems. We showed that KAR-2 impeded specifically the cell division. On the other hand, we elucidated the transport mechanisms of KAR-2 as compared to vinblastine, applying pharmacokinetic modelling based upon the combination of the data obtained from in situ animal and in vitro cell level experiments. The Caco-2 cell line and in in situ intestinal perfusion experiments in rat small intestine showed that vinblastine and KAR-2 are substrates of secretion transporters but with different affinity and KAR-2 presents a higher passive diffusion permeability. The information obtained from the kinetic modelling of each type of experiments rendered it possible to apply a single mathematical model to the whole (in vitro and in situ) data set including the adequate scale-up parameters. The model was validated by means of a model selection procedure based on the goodness of fit indexes to the experimental data. This unified quantitative model which characterizes the absorption/efflux features of KAR-2 as compared to vinblastine revealed its more favourable intestinal permeability. In addition, our pharmacokinetic analyses evaluated in this study showed the advantages of the modelling approach in maximizing of the information obtained from experimental data.
Gonzalez-Alvarez
Isabel
I
Department Ingeniería, Area Farmacia y Tecnología Farmacéutica, Universidad Miguel Hernández, Ctra. Alicante-Valencia, Alicante, Spain.
Gonzalez-Alvarez
Marta
M
Oltra-Noguera
Davinia
D
Merino
Virginia
V
Tõkési
Natália
N
Ovádi
Judit
J
Bermejo
Marival
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007267:Injections; D007408:Intestinal Absorption; D008297:Male; D015233:Models, Statistical; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence; D008941:Spindle Apparatus / Q000187:drug effects*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; C107832:deacetoxyvinzolidine