Oral Absorption of Clarithromycin Is Nearly Abolished by Chronic Comedication of Rifampicin in Foals

Abstract

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 g/ml), and BALC (10.2 ؎ 10.2 g/ml 264 ؎ 375 g/ml; all P < 0.05) were lowered drastically, whereas levels of the metabolite 14-hydroxyclarithromycin were not elevated despite higher 4␤-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.

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

“…We and others found that plasma exposure with 14OH-CLR (AUC and trough levels) was almost not influenced by RIF, after either short-term or long-term coadministration, although CLR absorption was dramatically reduced (Wallace et al, 1995;Taki et al, 2007;Peters et al, 2011); the lower AUC 0 -12h in our chronic study is explained by a decreased half-life of 14OH-CLR after induction of its terminal metabolism (Ferrero et al, 1990). It might be that the proximal intestine is the major site of CLR hydroxylation in horses, where CYP3A metabolic activity is highly expressed (Tydén et al, 2004).…”

“…Thirdly, the terminal elimination of 14OH-CLR by cytochrome P450 enzymes (N-demethylation and hydroxylation) was unchanged after short-term coadministration of RIF (7.28 Ϯ 1.35 versus 6.60 Ϯ 1.76 h; n.s.) but was significantly decreased after long-term treatment (8.11 Ϯ 1.61 versus 5.10 Ϯ 0.88 h; p Ͻ 0.05) (Suzuki et al, 2003;Peters et al, 2011). Therefore, the increased proportion of 14OH-CLR exposure (AUC 0 -12h ) relative to the AUC of total CLR (0.52 Ϯ 0.13 versus 0.21 Ϯ 0.06, p Ͻ 0.01) is most likely not caused by induction of CYP3A4 hydroxylation of CLR (Suzuki et al, 2003), and induction of presystemic metabolism of CLR is not the major reason for the Ͼ70% decrease in bioavailability (alternative reasons are noted in the discussion below).…”

“…Therefore, we evaluated the oral absorption and pulmonary distribution of clarithromycin (CLR) at steady state before and after longterm coadministration of rifampicin (RIF) in foals, because CLR is a substrate for cytochrome P450 3A4 and for the efflux transporters ABCB1 and likely ABCC2, which are expressed in enterocytes, hepatocytes, BECs, and BALCs and which can be induced by chronic treatment with the pregnane-X receptor (PXR) ligand RIF (Urquhart et al, 2007;Peters et al, 2011). Pharmacokinetic studies in foals are suitable for predicting transporter variability in human beings, because the foals' body size enables noninvasive experimental procedures, because protein homology and expression of drug transporters in horses are similar to those in rodents and humans, and because protein expression is regulated at a transcriptional level (Tydén et al, 2009(Tydén et al, , 2010.…”

Activity of Clarithromycin or Rifampin Alone or in Combination against Experimental Rhodococcus equi Infection in Mice

“…CLR is often selected over other macrolides because of its greater in vitro activity against R. equi (6) and because a retrospective study in foals suggests that, in combination therapy with RIF, CLR is more effective than other macrolides (8). However, in both people and foals, concurrent administration of RIF considerably reduces CLR concentrations compared to concentrations achieved with CLR monotherapy (14)(15)(16). This has raised the question of whether administration of RIF in addition to CLR is necessary, or even advisable, for the treatment of infections caused by R. equi.…”

“…All mice were weighed every 48 h. Treatments were RIF alone (10 mg/kg of body weight), CLR alone (25 mg/kg), combination therapy with CLR-RIF (25 mg/kg and 10 mg/kg, respectively), and 0.9% NaCl (control). The dosages and dosing intervals used were those likely to result in plasma drug concentrations similar to those achieved with the use of these antimicrobial agents in combination in horses and people (14,15,20,21). All treatments were diluted to an injection volume of 0.1 ml.…”