Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans

Abstract

Co-administration of thiabendazole or artemisinin with CYP1A2 substrates could result in clinically significant effects. Our results highlight the validity of in vitro data in predicting in vivo CYP inhibition. The formation of paraxanthine seems to be a better indicator of in vivo CYP1A2 activity than caffeine levels.

In Vitro and in Silico Identification and Characterization of Thiabendazole as a Mechanism-Based Inhibitor of CYP1A2 and Simulation of Possible Pharmacokinetic Drug-Drug Interactions

“…6), an indication the inactivation occurred via a catalytic process. The K I value determined for TBZ (1.4 M) was lower than the total plasma concentrations the drug is capable of reaching (19 M) (Bapiro et al, 2005). The k inact value of 0.08 min Ϫ1 is relatively high, such that the resulting k inact /K I of 0.05 M/min is predictive of likely significant enzyme inactivation.…”

“…TBZ has been reported to be a potent and mixed inhibitor of CYP1A2 both in vitro and in vivo (Bapiro et al, 2001(Bapiro et al, , 2005. The docking results could explain the observed results.…”

“…In vivo coadministration of thiabendazole with CYP1A2 substrate drugs was only available for caffeine and theophylline. This was followed by modeling where we mimicked published experimental methodology (e.g., dose, interval, duration, sample size) when the thiabendazole was administered alone (Tocco et al, 1966) or in combination with theophylline (Schneider et al, 1990) and caffeine (Bapiro et al, 2005). A fasted virtual Caucasian population was used in all the simulations.…”

“…A recent study has shown the potential for the inhibition of drug metabolism by TBZ to cause clinically important interactions with CYP1A2 substrates (Bapiro et al, 2005). TBZ has been shown to increase theophylline serum levels (2-3-fold, resulting in serious side effects) (Lew et al, 1989;Schneider et al, 1990).…”

Interactions of Theophylline with Drug, Diet, Some Xenobiotics, and Habits and Their Toxicological Outcomes

“…Gatifloksazin, levofloksazin, lomefloksazin, ofloksazin ve sparfloksazinin teofilin metabolizmasını çok daha az oranda inhibe ettiği, dolayısıyla teofilin metabolizmasına etkisinin çok az olduğu bildirilmiştir [10][11][12][13]. Diğer ilaçlar: Etinil östradiol, simetidin[2], flovuksamin [2,14], tiklopidin [15], alosetron [16], izoniazid [2,17], allopürinol***[2], meksiletin, oral kontraseptifler [18], tiyobendazol [19], tacrin, troleandomisin, zileuton [11].…”