Metabolism and interactions of Ivermectin with human cytochrome P450 enzymes and drug transporters, possible adverse and toxic effects

Abstract

The review presents metabolic properties of Ivermectin (IVM) as substrate and inhibitor of human P450 (P450, CYP) enzymes and drug transporters. IVM is metabolized, both in vivo and in vitro, by C-hydroxylation and O-demethylation reactions catalyzed by P450 3A4 as the major enzyme, with a contribution of P450 3A5 and 2C9. In samples from both in vitro and in vivo metabolism, a number of metabolites were detected and as major identified metabolites were 3″-O-demethylated, C4-methyl hydroxylated, C25 isobutyl-/isopropyl-hydroxylated, and products of oxidation reactions. Ivermectin inhibited P450 2C9, 2C19, 2D6, and CYP3A4 with IC 50 values ranging from 5.3 μM to no inhibition suggesting that it is no or weak inhibitor of the enzymes. It is suggested that P-gp (MDR1) transporter participate in IVM efflux at low drug concentration with a slow transport rate. At the higher, micromolar concentration range, which saturates MDR1 (P-gp), MRP1, and to a lesser extent, MRP2 and MRP3 participate in IVM transport across physiological barriers. IVM exerts a potent inhibition of P-gp (ABCB1), MRP1 (ABCC1), MRP2 (ABCC2), and BCRP1 (ABCG2), and medium to weak inhibition of OATP1B1 (SLC21A6) and OATP1B3 (SLCOB3) transport activity. The metabolic and transport properties of IVM indicate that when IVM is co-administered with other drugs/chemicals that are potent inhibitors/inducers P4503A4 enzyme and of MDR1 (P-gp), BCRP or MRP transporters, or when polymorphisms of the drug transporters and P450 3A4 exist, drug–drug or drug–toxic chemical interactions might result in suboptimal response to the therapy or to toxic effects.

Cytochrome P450 Enzymes and Drug Metabolism in Humans

“…The majority of drugs lipophilic centers are converted to hydrophilic centers during drug biotransformation, which can increase their water solubility, to allow elimination in urine or bile [ 3 ]. This is an important progress for drug metabolism, because the lipophilic nature of drugs can keep them staying for longer in the body, which may in turn lead to toxicity [ 4 , 5 ]. Drug metabolism can be divided into phase I and phase II reactions [ 6 ].…”

Assessment of Avermectins-Induced Toxicity in Animals

“…It is used to treat health conditions like onchocerciasis, strongyloidiasis, lymphatic filariasis, and crusted scabies [ 10 , 21 , 22 , 23 ]. As far as the toxicity is concerned in humans, ivermectin damages the macrophages and interacts with liver cytochrome P450 enzymes, thus producing immunotoxicity and hepatotoxicity [ 24 , 25 ]. Other clinical signs observed in patients receiving ivermectin therapy may include pruritis, malaise, skin edema, hypotension, headache, and dyspnea [ 21 ].…”

A possível citotoxicidade desenvolvida pelo uso de ivermectina em pacientes com COVID-19: uma revisão integrativa

“…al 2022). O processo metabólico da Ivermectina pode causar interações com transportadores de drogas e interações droga-droga/droga-química e toxicidade, que podem ocorrer em uma ampla gama de suas aplicações clínicas (Rendic, et. al 2021;Zaidi & Dehgani-Mobaraki, 2021).…”

“…Considerando esta dinâmica do medicamento e a pandemia do COVID-19 com número de mortes alarmantes, foi sugerido, em meados de 2020, o uso da ivermectina para o tratamento inicial de pacientes infectados com sintomas leves e moderados por COVID-19 (Medeiros et al, 2021). Research, Society andDevelopment, v. 11, n. 11, e555111133611, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i11.33611 3 As doses inicias administradas em seres humanos para se ter o resultado esperado devem ter maiores concentração em comparação as aplicadas nas células in vitro, entretanto, essa elevada concentração medicamentosa tem efeito tóxico para o organismo dos pacientes (Molento, 2020), haja vista que, segundo Rendic (2021) a farmacocinética e o metabolismo hepático da ivermectina nos seres humanos podem ter ação inibitória através da neurotransmissão GABAenérgico, resultando na liberação do GABA, o qual age como agonista e promove a neurotoxicidade, quando executada em altas doses, devido a sua capacidade absorção-expulsão pelo trato gastrointestinal e barreira hematoencefálica que é mediada por P-gp, MRPs, ABCB1 e outros transportadores ABC.…”