Oral absorption of clarithromycin is nearly abolished by chronic comedication of rifampicin in foals.
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 (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.
Publication Date: 2011-06-20 PubMed ID: 21690264DOI: 10.1124/dmd.111.039206Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research investigates the impact of long-term combined use of rifampicin (an antibiotic) on the oral absorption of clarithromycin (an antibiotic) in foals. It reveals that rifampicin significantly hinders the absorption and distribution of clarithromycin into the lung cells, reducing its effectiveness.
Introduction and Methodology
- The study focuses on how the effectiveness of clarithromycin, a common antibiotic, can be significantly affected by rifampicin, another antibiotic. It delves into the dynamics of two drug transporters (ABCB1 and ABCC2) and organic anion-transporting polypeptides (OATPs).
- Rifampicin can both modulate and up-regulate these elements via the nuclear pregnane X receptor (PXR), potentially influencing the delivery of clarithromycin to the lungs.
- The researchers conducted the study on nine healthy foals whose genetic homology to these drug transporters closely resembles that of humans.
- The foals were given doses of clarithromycin for 21 days, while also receiving rifampicin for 11 days. The researchers monitored the distribution of clarithromycin and the expression of the drug transporters before and after rifampicin medication.
Findings
- Post-rifampicin medication, the bioavailability of clarithromycin dropped by over 90%, implying that the drug’s absorption was significantly hindered.
- Concentrations of clarithromycin in plasma, ELF, and BALC were drastically lowered. However, levels of the metabolite 14-hydroxyclarithromycin were not elevated despite higher plasma concentration ratios.
- The mRNA contents of ABCC2 and PXR were significantly and coordinately reduced in BALC after the administration of rifampicin, while in EC, the mRNA expression of OATP1A2 increased, but that of OATP2B1 decreased.
- The study reveals that rifampicin has a powerful impact on the oral absorption and cellular uptake of clarithromycin in bronchial cells, compromising its effectiveness.
Conclusion
- The take-home message of this research is that the chronic co-administration of rifampicin can largely interrupt the oral absorption of clarithromycin in foals. This can lead to reduced plasma levels of clarithromycin, rendering it less effective in the eradication of certain bacteria, such as Rhodococcus equi.
- The study indicates that careful consideration should be given when prescribing rifampicin and clarithromycin together due to the potential negative impacts on drug absorption and function.
Cite This Article
APA
Peters J, Block W, Oswald S, Freyer J, Grube M, Kroemer HK, Lämmer M, Lütjohann D, Venner M, Siegmund W.
(2011).
Oral absorption of clarithromycin is nearly abolished by chronic comedication of rifampicin in foals.
Drug Metab Dispos, 39(9), 1643-1649.
https://doi.org/10.1124/dmd.111.039206 Publication
Researcher Affiliations
- Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany.
MeSH Terms
- ATP-Binding Cassette Transporters / metabolism
- Absorption / drug effects
- Animals
- Bronchi / metabolism
- Cholesterol / blood
- Clarithromycin / analogs & derivatives
- Clarithromycin / metabolism
- Clarithromycin / pharmacokinetics
- Drug Interactions
- Epithelial Cells / drug effects
- Epithelial Cells / metabolism
- Horses / metabolism
- Hydroxycholesterols / blood
- Lung / metabolism
- Mouth Mucosa / drug effects
- Mouth Mucosa / metabolism
- Multidrug Resistance-Associated Protein 2
- Organic Anion Transporters / genetics
- Organic Anion Transporters / metabolism
- Pregnane X Receptor
- RNA, Messenger / genetics
- Receptors, Steroid / metabolism
- Rifampin / pharmacology
Citations
This article has been cited 6 times.- Rosa B. Equine Drug Transporters: A Mini-Review and Veterinary Perspective.. Pharmaceutics 2020 Nov 8;12(11).
- Rampacci E, Marenzoni ML, Chiaradia E, Passamonti F, Ricci M, Pepe M, Coletti M, Giovagnoli S. In vitro performances of novel co-spray-dried azithromycin/rifampicin microparticles for Rhodococcus equi disease treatment.. Sci Rep 2018 Aug 14;8(1):12149.
- Salerno SN, Edginton A, Cohen-Wolkowiez M, Hornik CP, Watt KM, Jamieson BD, Gonzalez D. Development of an Adult Physiologically Based Pharmacokinetic Model of Solithromycin in Plasma and Epithelial Lining Fluid.. CPT Pharmacometrics Syst Pharmacol 2017 Dec;6(12):814-822.
- Benson EA, Eadon MT, Desta Z, Liu Y, Lin H, Burgess KS, Segar MW, Gaedigk A, Skaar TC. Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes.. Front Pharmacol 2016;7:111.
- Burton AJ, Giguère S, Berghaus LJ, Hondalus MK. Activity of clarithromycin or rifampin alone or in combination against experimental Rhodococcus equi infection in mice.. Antimicrob Agents Chemother 2015;59(6):3633-6.
- Rodvold KA, Gotfried MH, Still JG, Clark K, Fernandes P. Comparison of plasma, epithelial lining fluid, and alveolar macrophage concentrations of solithromycin (CEM-101) in healthy adult subjects.. Antimicrob Agents Chemother 2012 Oct;56(10):5076-81.
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