Clarithromycin Is Absorbed by an Intestinal Uptake Mechanism That Is Sensitive to Major Inhibition by Rifampicin: Results of a Short-Term Drug Interaction Study in Foals

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 4β-hydroxycholesterol/cholesterol ratio (a surrogate for CYP3A4 induction). CLR was an inhibitor of OATP1B3 (IC50 = 9.50 ± 3.50 μM), OATP1B1 (IC50 = 46.0 ± 2.27 μM), OATP1A2 (IC50 = 92.6 ± 1.49 μM), and OATP2B1 (IC50 = 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.

[1]  Elise A Lee,et al.  Pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar cells of foals. , 2001, American journal of veterinary research.

[2]  K. Chiba,et al.  CYP isoforms involved in the metabolism of clarithromycin in vitro: comparison between the identification from disappearance rate and that from formation rate of metabolites. , 2003, Drug metabolism and pharmacokinetics.

[3]  P. Watkins,et al.  Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. , 2006, The Journal of clinical investigation.

[4]  S. Giguère,et al.  In Vitro Susceptibilities of Rhodococcus equi and Other Common Equine Pathogens to Azithromycin, Clarithromycin, and 20 Other Antimicrobials , 2003, Antimicrobial Agents and Chemotherapy.

[5]  T. Nikai,et al.  [Clinical analysis of drug interaction between rifampicin and clarithromycin which are used for treating pulmonary Mycobacterium avium complex infection]. , 2007, Kekkaku : [Tuberculosis].

[6]  L. Bertilsson,et al.  4beta-hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin. , 2009, British journal of clinical pharmacology.

[7]  Jorge A. Hernandez,et al.  Retrospective comparison of azithromycin, clarithromycin, and erythromycin for the treatment of foals with Rhodococcus equi pneumonia. , 2004, Journal of Veterinary Internal Medicine.

[8]  D. Baldwin,et al.  Rifampicin concentrations in bronchial mucosa, epithelial lining fluid, alveolar macrophages and serum following a single 600 mg oral dose in patients undergoing fibre-optic bronchoscopy. , 2002, The Journal of antimicrobial chemotherapy.

[9]  M. Venner,et al.  LC-MS/MS method for the simultaneous determination of clarithromycin, rifampicin and their main metabolites in horse plasma, epithelial lining fluid and broncho-alveolar cells. , 2011, Journal of pharmaceutical and biomedical analysis.

[10]  Markus Grube,et al.  Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters , 2010, Drug Metabolism and Disposition.

[11]  H. Kroemer,et al.  Oral Absorption of Clarithromycin Is Nearly Abolished by Chronic Comedication of Rifampicin in Foals , 2011, Drug Metabolism and Disposition.

[12]  D. Anderson,et al.  Metabolism and disposition of clarithromycin in man. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[13]  R. Crystal,et al.  Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. , 1986, Journal of applied physiology.

[14]  S. Vavricka,et al.  Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver , 2002, Hepatology.

[15]  U. Fuhr,et al.  Plasma 4β‐Hydroxycholesterol: An Endogenous CYP3A Metric? , 2009, Clinical pharmacology and therapeutics.

[16]  S. Giguère,et al.  Pharmacokinetics of azithromycin and concentration in body fluids and bronchoalveolar cells in foals. , 2001, American journal of veterinary research.

[17]  D. Postma,et al.  ATP-binding cassette (ABC) transporters in normal and pathological lung , 2005, Respiratory research.

[18]  J. Tallkvist,et al.  P-glycoprotein in intestines, liver, kidney and lymphocytes in horse. , 2009, Journal of veterinary pharmacology and therapeutics.

[19]  H. Glaeser,et al.  Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. , 2010, Biochemical pharmacology.

[20]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[21]  P. Dawson,et al.  Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat , 2008, Drug Metabolism and Disposition.

[22]  A. D. Rodrigues,et al.  Does the Long Plasma Half‐Life of 4β‐Hydroxycholesterol Impact Its Utility as a Cytochrome P450 3A (CYP3A) Metric? , 2010, Journal of clinical pharmacology.

[23]  Oliver Burk,et al.  Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin* , 2001, The Journal of Biological Chemistry.

[24]  Paul T Tarr,et al.  Regulation of Multidrug Resistance-associated Protein 2 (ABCC2) by the Nuclear Receptors Pregnane X Receptor, Farnesoid X-activated Receptor, and Constitutive Androstane Receptor* , 2002, The Journal of Biological Chemistry.

[25]  H. Tjälve,et al.  Expression and localization of BCRP, MRP1 and MRP2 in intestines, liver and kidney in horse. , 2010, Journal of veterinary pharmacology and therapeutics.

[26]  P. Dawson,et al.  Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides , 2009, Drug Metabolism and Disposition.

[27]  R. Wallace,,et al.  Reduced serum levels of clarithromycin in patients treated with multidrug regimens including rifampin or rifabutin for Mycobacterium avium-M. intracellulare infection. , 1995, The Journal of infectious diseases.

[28]  C. Macallister,et al.  Rifampin disposition in the horse: effects of repeated dosage of rifampin or phenylbutazone. , 1992, Journal of veterinary pharmacology and therapeutics.

[29]  Werner Weitschies,et al.  Disposition and sterol‐lowering effect of ezetimibe are influenced by single‐dose coadministration of rifampin, an inhibitor of multidrug transport proteins , 2006, Clinical pharmacology and therapeutics.

[30]  Sean Kim,et al.  CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[31]  Y. Takiguchi,et al.  Carbapenem antibiotics inhibit valproic acid transport in Caco-2 cell monolayers. , 2002, International journal of pharmaceutics.

[32]  L. Mikac,et al.  Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[33]  Bradley L Urquhart,et al.  Nuclear Receptors and the Regulation of Drug‐Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs , 2007, Journal of clinical pharmacology.

[34]  Martin F. Fromm,et al.  The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3 , 2007, Drug Metabolism and Disposition.

[35]  G. Acocella.  Clinical Pharmacokinetics of Rifampicin , 1978, Clinical pharmacokinetics.

[36]  J. Tallkvist,et al.  CYP3A in horse intestines. , 2004, Toxicology and applied pharmacology.

[37]  R. Kim,et al.  Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. , 2008, Cancer research.

[38]  L. Bertilsson,et al.  Cytochrome P450 Induction by Rifampicin in Healthy Subjects: Determination Using the Karolinska Cocktail and the Endogenous CYP3A4 Marker 4β‐Hydroxycholesterol , 2008, Clinical pharmacology and therapeutics.