Abstract
The delivery of clarithromycin (CRL) to its site of action in bronchial/alveolar epithelial cells (EC), bronchial epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) may be influenced by CYP3A4 and the drug transporters ABCB1, ABCC2 and OATPs which can be modulated and/or upregulated via the nuclear pregnane X receptor (PXR) by rifampicin (RIF). Therefore, we evaluated disposition and pulmonary distribution of CLR (7.5 mg/kg b.i.d., 21 days) and expression of ABCB1, ABCC2, OATP1A2 and OATP2B1 in EC and BALC before and after comedication of RIF (10 mg/kg b.i.d., 11 days) in 9 healthy foals (41-61 days, 115-159 kg) in which the genetic homology of drug transporters is close to their human analogs. After RIF comedication, relative bioavailability of CLR decreased by more than 90%. Concentrations in plasma (29.8±26.3 ng/ml vs. 462±368 ng/ml), ELF (0.69±0.66 µg/ml vs. 9.49±6.12 µg/ml) and BALC (10.2±10.2 µg/ml vs. 264±375 µg/ml, all p<0.05) were lowered drastically whereas levels of the metabolite 14-hydroxyclarithromycin (14OH-CLR) were not elevated despite higher 4β-OH-cholesterol/cholesterol plasma concentration ratio, a surrogate for CYP3A4 induction. In presence of CLR, ABCC2 and PXR mRNA content were significantly and coordinately (r2=0.664, p<0.001) reduced in BALC after RIF. In EC, mRNA expression of OATP1A2 increased but of OATP2B1 decreased (both p<0.05). RIF interrupts oral absorption and decreases CRL plasma levels below the minimal inhibitory concentration for eradication of Rhodococcus equi. Evidence exists for RIF to influence the cellular uptake of CLR in bronchial cells and the PXR expression in BALC in presence of high CLR concentrations.
- Received March 2, 2011.
- Accepted June 20, 2011.
- The American Society for Pharmacology and Experimental Therapeutics