Estudo farmacocinético do protótipo de fármaco antineoplástico LQFM018 em modelos pré-clínicos
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| Auteur principal: | |
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| Date de publication: | 2016 |
| Format: | Doctoral thesis |
| Langue: | por |
| Source: | Repositório Institucional da UFG |
| Download full: | http://repositorio.bc.ufg.br/tede/handle/tede/13999 |
Résumé: | LQFM 018 is an antitumor prototype synthesized from molecular simplification of nutlin-3a and demonstrated activity against K-562 leukemia cells. This work sought to evaluate LQFM018 pharmacokinetics and bioavailability in mice and to determine possible drug interactions it maybe will cause when administered along with drugs metabolized by CYP3A microsomal enzymes family. For this purpuse, LQFM018 solutions were injected in mice via a tail vein at a single dose of 10 mg/kg (i.v.); intraperitoneally at doses of 25, 50 and 100 mg/kg (i.p.) and orally at a dose of 100 mg/kg (p.o.). Blood samples were collected over 24 hours by cardiac punction and LQFM018 concentration were determined by validated HPLC MS/MS method. The following pharmacokinetics parameters were obtained by WinNonlin 5.0 software (Pharsight): area under the time vs concentration curve (AUCT), maximal concentration (Cmax) and time to reach it (Tmax), apparent volume of distribution (Vd), elimination half-life (t1/2) and total clearance (ClT). Absolute bioavailability were calculated by bioavailable fraction of the systemic circulation (F%). Results were extrapolated to humans by allometric scale. AUCT values were proportional to dose after i.p. administration suggesting linear kinetics. The mean elimination half-lives were 4.37 ± 0.11 h p.o. and i.p., and 1.5 ± 0.45 h i.v. For extravascular administrations, Vd = 5.33 ± 1.05 L/kg, F values were 41.0 ± 6.98 % suggesting pre-systemic elimination (ClT values were 13.9 ± 2.76 mL/min/kg). Double peaks in time versus concentration curve, at elimination phase, suggest enterohepatic recirculation. In order to verify the ability of LQFM018 to inhibit liver enzyme CYP3A in rats, this enzymes were tested as the capacity of midazolam metabolization in the presence and in the absence of LQFM018 for evaluate inhibitory effect. LQFM018 demonstrated partial inhibitory activity on in vitro CYP3A enzymes when the highest concentration was tested (100 µg/mL). In LQFM018 average concentration (50 µg/mL) there was 56% of inhibition; LQFM018 tested at low concentration (10 µg/mL) did not interfere with the metabolism of CYP3A enzymes. The results show that LQFM018 is an antitumor prototype highly distributed (with great penetrating power, due to its apparent high Vd) may be used in the future for the treatment of deep tumors. Its high value of CLT shows that it is quickly eliminated, which is corroborated by the low value of t1/2 . These features combined with linear kinetics are pharmacokinetic advantages, but its high Vd values suggests that this molecule can undergo accumulation in tissues. The enterohepatic circulation and the ability to inhibit CYP3A enzymes by LQFM018 are parameters to be evaluated when administered in multiple doses. This work should provide a basis for future LQFM018 pharmacokinetic tests. |
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