Abstract
Macrocyclic lactones (MLs) are lipophilic anthelmintics and substrates for P-glycoprotein (P-gp), an ABC transporter involved in drug efflux out of both host and parasites. In order to evaluate the contribution of P-gp to the in vivo kinetic disposition of MLs, the plasma kinetics, brain concentration and intestinal excretion of three structurally different MLs (ivermectin, eprinomectin and moxidectin) were compared in wild-type and P-gp deficient (mdr1ab-/-) mice. Each drug (0.2 mg/kg) was administered orally, intravenously or subcutaneously to the mice. Plasma, brain and intestinal tissue concentrations were measured by HPLC. The intestinal excretion rate following intravenous administration was determined at different levels of the small intestine by using an in situ intestinal perfusion model. P-gp deficiency led to a significant increase in the area under the plasma concentration-time curve (AUC) of ivermectin (1.5 fold) and eprinomectin (3.3 fold) while the moxidectin AUC was unchanged. Interestingly, ivermectin, and to a greater extent eprinomectin, were both excreted by the intestine via a P-gp-dependent pathway while moxidectin excretion was weaker and mostly P-gp independent. The three drugs accumulated in the brains of the mdr1ab-/- mice but eprinomectin concentrations were significantly lower. We concluded that eprinomectin disposition in mice is mainly controlled by P-gp efflux, more so than ivermectin, while moxidectin disposition appears to be mostly P-gp-independent. Given that eprinomectin and ivermectin have higher affinity for P-gp than moxidectin, these findings demonstrated that the relative affinity of MLs for P-gp could be predictive of the in vivo kinetic behaviour of these drugs.
- ABC transporters
- absorption
- active transport
- bioavailability
- blood-brain barrier
- drug disposition
- drug distribution
- drug efflux
- p-glycoprotein
- pharmacokinetics
Footnotes
- Received October 13, 2009.
- Accepted January 20, 2010.
- The American Society for Pharmacology and Experimental Therapeutics