Farmakokinetika rastućih doza metotreksata nakon intravenske primene kod pacova – odabir modela

  • Ivana Rajšić University of Novi Sad, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Novi Sad, Serbia
  • Nebojša Pavlović University of Novi Sad, Faculty of Medicine, Department of Pharmacy, Faculty of Technical Sciences, Novi Sad, Serbia
  • Boris Milijašević University of Novi Sad, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Novi Sad, Serbia
  • Saša Vukmirović University of Novi Sad, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Novi Sad, Serbia
  • Dragan Spasić University of Novi Sad, Faculty of Medicine, Department of Mechanics, Novi Sad, Serbia
  • Miodrag Žigić University of Novi Sad, Faculty of Medicine, Department of Mechanics, Novi Sad, Serbia
  • Nenad Grahovac University of Novi Sad, Faculty of Medicine, Department of Mechanics, Novi Sad, Serbia
  • Svetlana Goločorbin-Kon University of Novi Sad, Faculty of Medicine, Department of Pharmacy, Faculty of Technical Sciences, Novi Sad, Serbia
  • Momir Mikov University of Novi Sad, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Novi Sad, Serbia
DOI: https://doi.org/10.2298/VSP190430126R
Ključne reči: metotreksat, lekovi, odnos doza-reakcija, modeli, biološki, lečenje, ishod, pacovi

Sažetak


Uvod/Cilj. Metotreksat (MTX) ima značajnu ulogu u lečenju različitih bolesti, ali toksičnost predstavlja glavni ograničavajući faktor njegove primene, naročito kada se primenjuje u visokim dozama. Imajući u vidu izmenjenu farmakokinetiku MTX, kao faktora koji je snažno povezan sa značajnom varijabilnošću kliničkog odgovora i neočekivanom toksičnošću kod određenih bolesnika, tačan opis farmakokinetičkog ponašanja MTX primenjenog u niskim i visokim dozama je od izuzetnog značaja. Stoga je cilj ove studije bio da se odredi farmakokinetika MTX nakon intravenske (iv) primene u rastućim dozama od 5, 40, 80 i 160 mg/kg kod pacova i da se odabere odgovarajući matematički model koji dobro opisuje farmakokinetiku ovog leka. Metode. Koncentracije MTX u plazmi su merene korišćenjem tečne hromatografije kuplovane sa masenom spektrometrijom (LC/MS). Farmakokinetički parametri su izračunati pomoću neprostornih i dvoprostornih celobrojnih matematičkih analiza. Rezultati. MTX je pokazao linearnu farmakokinetiku koja prati iv primenjene doze do 80 mg/kg. Davanje visoke doze MTX (160 mg/kg) rezultiralo je sličnim farmakokinetičkim ponašanjem kao kada se primenjuje u dvostruko nižoj dozi (80 mg/kg), što se može objasniti dozno-zavisnim promenama u ekspresiji SLC i ABC transportnih proteina i intracelularnom metabolizmu ovog leka. Osim toga, klasični model sa dva kompartmana nije mogao da objasni farmakokinetiku MTX kod malog procenta eksperimentalnih životinja, što otvara nove mogućnosti za korišćenje frakcionih farma kokinetičkih modela u optimizaciji MTX terapije. Zaključak. Dobijeni rezultati farmakokinetičkih analiza na životinjama mogu biti korisni u prilagođavanju režima doziranja MTX, ali je primena novih farmakokinetičkih modela, poput onih baziranih na frakcionom računu, kao i određivanje farmakokinetičkog ponašanja MTX kod različitih bolesnika, neophodno u procesu pune optimizacije terapije ovim lekom.

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2021/08/06
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Vol. 78 Br. 7 (2021): Vojnosanitetski pregled
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