Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae
Chaccour CJ (1,2,3), Hammann F (4), Alustiza M (5), Castejon S (6), Tarimo BB (7), Abizanda G (8), Irigoyen Barrio Á (9), Martí Soler H (10), Moncada R (11), Bilbao JI (12), Aldaz A (13), Maia M (7,14,15,16), Del Pozo JL (6,17).
(1) Instituto de Salud Tropical, Universidad de Navarra, Pamplona, 31008, Spain.
(2) ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, 08036, Spain.
(3) Centro de Investigação em Saúde de Manhiça, Maputo, 1929, Mozambique.
(4) Division of Clinical Pharmacology and Toxicology, University Hospital Basel and University of Basel, Basel, 4056, Switzerland.
(5) Faculty of Medicine, Universidad de Navarra, Pamplona, 31008, Spain.
(6) Department of Microbiology, Clínica Universidad de Navarra, Pamplona, 31008, Spain.
(7) Ifakara Health Institute, Bagamoyo, Pwani, P.O. Box 74, United Republic of Tanzania.
(8) Centro de Investigación Médica Aplicada, Pamplona, 31008, Spain.
(9) Drug Development Unit Universidad de Navarra (DDUNAV), Pamplona, 31008, Spain.
(10) ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, 08036, Spain.
(11) Department of Anaesthesia, Clínica Universidad de Navarra, Pamplona, 31008, Spain.
(12) Department of Radiology, Clínica Universidad de Navarra, Pamplona, 31008, Spain.
(13) Department of Pharmacy, Clínica Universidad de Navarra, Pamplona, 31008, Spain.
(14) Swiss Tropical and Public Health Institute, Basel, 4051, Switzerland.
(15) University of Basel, Basel, 4003, Switzerland.
(16) KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.
(17) Infectious Diseases Division, Clínica Universidad de Navarra, Pamplona, 31008, Spain.
Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission.
Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes.
Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations.
In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae.
This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes.
Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems.
Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.
CITA DEL ARTÍCULO Sci Rep. 2017 Aug 17;7(1):8535. doi: 10.1038/s41598-017-08906-x