ABSTRACT
Pulmonary penetration of clarithromycin (CLR) in epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALCs) can be influenced by CYP3A4, by P-glycoprotein, and, according to our hypothesis, by a member of the organic anion-transporting protein (OATP) family, for which rifampicin (RIF) is inhibiting in single doses but inducing after long-term coadministration. To assess the partial inhibitory effect, we measured absorption and pulmonary distribution of CLR after short-term (2.5-day) coadministration of RIF, after which up-regulation is not expected. The drug interaction study was performed with five doses (12-h interval) of CLR (7.5 mg/kg) and RIF (10 mg/kg) in nine healthy foals; horse transporters are very similar in protein sequence and transcriptional regulation to the human analogs. RIF was equally distributed in ELF but reached half the plasma levels in BALCs. The deacetylated metabolite accumulated 1.4- to 6-fold in ELF and 8- to 60-fold in BALCs. CLR did not significantly influence the distribution of RIF. CLR and 14-hydroxyclarithromycin (14OH-CLR) accumulated approximately 20- to 40-fold and 1.5- to 4.5-fold in ELF and 300- to 1800-fold and 25- to 90-fold in BALCs, respectively. With RIF, plasma levels of CLR decreased by more than 70% without changes in 14OH-CLR formation, the half-lives of CLR and 14OH-CLR, and the 4ß-hydroxycholesterol/cholesterol ratio (a surrogate for CYP3A4 induction). CLR was an inhibitor of OATP1B3 (IC(50) = 9.50 ± 3.50 µM), OATP1B1 (IC(50) = 46.0 ± 2.27 µM), OATP1A2 (IC(50) = 92.6 ± 1.49 µM), and OATP2B1 (IC(50) = 384 ± 5.30 µM) but was not a substrate for these transporters in transfected human embryonic kidney cells. In conclusion, despite having no significant inducing effects, RIF decreased plasma levels of CLR below the minimal inhibitory concentration required to inhibit 90% of growth of pathogenic bacteria, most likely through inhibition of an unknown intestinal uptake transporter.
Subject(s)
Clarithromycin/pharmacokinetics , Intestinal Absorption/drug effects , Intestinal Mucosa/metabolism , Intestines/drug effects , Rifampin/pharmacology , Animals , Clarithromycin/analogs & derivatives , Clarithromycin/metabolism , Drug Interactions , Female , HEK293 Cells , Horses , Humans , Lung/drug effects , Lung/metabolism , Male , Organic Anion Transporters/metabolism , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Rifampin/pharmacokinetics , Transfection/methods , Up-Regulation/drug effectsABSTRACT
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, ATP-binding cassette (ABC) B1 and ABCC2 and organic anion-transporting polypeptides (OATPs), which can be modulated and/or up-regulated via the nuclear pregnane X receptor (PXR) by rifampicin (RIF). Therefore, we evaluated the 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 nine healthy foals (41-61 days, 115-159 kg) in which the genetic homology of drug transporters is close to that of their human analogs. After RIF comedication, relative bioavailability of CLR decreased by more than 90%. Concentrations in plasma (29.8 ± 26.3 versus 462 ± 368 ng/ml), ELF (0.69 ± 0.66 versus 9.49 ± 6.12 µg/ml), and BALC (10.2 ± 10.2 µg/ml 264 ± 375 µg/ml; all P < 0.05) were lowered drastically, whereas levels of the metabolite 14-hydroxyclarithromycin were not elevated despite higher 4ß-hydroxycholesterol/cholesterol plasma concentration ratio, a surrogate for CYP3A4 induction. In the presence of CLR, ABCC2 and PXR mRNA contents were significantly and coordinately (r(2) = 0.664, P < 0.001) reduced in BALC after RIF. In EC, mRNA expression of OATP1A2 increased but that 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 that RIF influences the cellular uptake of CLR in bronchial cells and the PXR expression in BALC in the presence of high CLR concentrations exists.