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, 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 4β-hydroxycholesterol/cholesterol plasma concentration ratio, a surrogate for CYP3A4 induction. In the presence of CLR, ABCC2 and PXR mRNA contents were significantly and coordinately (r2 = 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.
Footnotes
The clinical part of the study was supported by the Paul-Schockmoehle Lewitz Stud, Neustadt-Glewe, Germany. The analytical part and the molecular and cell biological part were supported by the German Federal Ministry for Education and Research [Grant 03IP612, InnoProfile].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039206.
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ABBREVIATIONS:
- MIC
- minimal inhibition concentration
- EC
- bronchial/alveolar epithelial cell(s)
- ELF
- epithelial lining fluid
- BALC
- bronchoalveolar lavage cell(s)
- OATP/Oatp
- organic anion transporting polypeptide
- OCT
- organic cation transporter
- ABC
- ATP-binding cassette
- CLR
- clarithromycin
- RIF
- rifampicin
- PXR
- pregnane X receptor
- 14-OH-CLR
- 14-hydroxyclarithromycin
- 4β-OH-C
- 4β-hydroxycholesterol
- RT
- reverse transcriptase
- PCR
- polymerase chain reaction
- AUC
- area under the plasma concentration-time curve.
- Received March 1, 2011.
- Accepted June 20, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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