RT Journal Article
SR Electronic
T1 ORAL ABSORPTION OF CLARITHROMYCIN IS NEARLY ABOLISHED BY CHRONIC COMEDICATION OF RIFAMPICIN IN FOALS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.111.039206
DO 10.1124/dmd.111.039206
A1 Jette Peters
A1 Wiebke Block
A1 Stefan Oswald
A1 Johanna Freyer
A1 Markus Grube
A1 Heyo K. Kroemer
A1 Marc Lammer
A1 Dieter Luetjohann
A1 Monica Venner
A1 Werner Siegmund
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/06/20/dmd.111.039206.abstract
AB 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.