Mechanisms of drug–drug interaction between rifampicin and fusidic acid

Tables of Links

TARGETS
Transporters 2
OATP1B1
Enzymes 3
CYP3A4

LIGANDS
Rifampicin

These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2, 3.

We have read with interest the article published by Marsot et al. 4 describing the development of a population pharmacokinetic model of rifampicin (RIF) in patients with osteoarticular infections. The authors have identified a drug–drug interaction (DDI) between rifampicin and fusidic acid (FA), the latter decreasing both RIF clearance and volume of distribution. The authors suggest that this interaction would be due to inhibition of cytochrome P450 3A4 (CYP3A4) by FA. However, there is little information supporting this assumption in the paper.

We would like to discuss further the mechanism of this interaction and suggest an alternative hypothesis.

First, it has been shown that RIF is mainly metabolized in the liver into a 25‐deacetyl form by esterases (human arylacetamide deacetylase) 5. RIF is also converted into 3‐formylrifampicin by non‐enzymatic hydrolysis 6, 7 and it is excreted partially unchanged in the bile and urine. While RIF is a well‐known potent CYP3A4 inducer, it does not appear to be a significant substrate of this enzyme. So, FA‐induced inhibition of CYP3A4 is unlikely to be the major mechanism of the DDI between RIF and FA.

It has been shown that RIF is a sensitive substrate of the organic anion transporting polypeptide (OATP) 1B1 8. This outward transporter [previously known as OATP2, OATP‐C and liver‐specific organic anion transporter (LST‐1) 9, 10] is expressed on the sinusoidal membrane of hepatocytes and is responsible for the uptake of drugs into the liver 10. Of note, RIF is also an inhibitor of this transporter 11.

In regard to RIF, two polymorphisms (rs4149032 and rs11045819) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, which encodes OATP1B1, have been associated with reduced RIF exposure due to decreased bioavailability 12, 13, which confirms the clinically significant influence of this transporter on RIF disposition.

Recently, Gupta et al. 14 have studied the inhibition potency of FA towards various metabolic and transporter pathways involved in statin pharmacokinetics. They elegantly showed that FA inhibits OATP1B1, as well as breast cancer resistance protein (BCRP) and CYP3A4. This may explain well the known interaction between FA and statins which may result in overexposure to statins and rhabdomyolysis. They also showed that FA is eliminated primarily by CYP3A4.

To summarize, as RIF is a sensitive substrate of OATP1B1 15 and FA is an inhibitor of this transporter, we assume that FA could reduce the hepatic uptake and presystemic clearance of RIF, resulting in increased bioavailability and plasma concentrations, as found by Marsot et al. 4. As FA also inhibits BCRP, a reduction in RIF biliary excretion may also participate in the interaction, but this remains to be proven.

Finally, it should be noted that a mutual interaction exists between RIF and FA, as RIF can induce the CYP3A4‐mediated metabolism of FA and lower FA concentrations 16.

To conclude, a complex mutual interaction appears to exist between RIF and FA, as summarized in Figure 1. On the one hand, FA can increase the RIF concentration. On the other hand, RIF can decrease the FA concentration. As RIF also induces its own metabolism, the time course, as well as the clinical consequences, of this mutual interaction are difficult to predict in individual patients, although the association has been associated with a favourable outcome in patients with methicillin‐resistant Staphylococcus aureus implant‐associated bone and joint infection 17. Therapeutic drug monitoring of both agents may be of interest for the clinical management of this interaction.

Figure 1.

Proposed mechanisms for the drug–drug interaction between rifampicin and fusidic acid. BCRP, breast cancer resistance protein; CYP3A4, cytochrome P450 3A4; OATP1B1, organic anion transporting polypeptide 1B1

Competing Interests

There are no competing interests to declare.

Bel, F. , Bourguignon, L. , Tod, M. , Ferry, T. , and Goutelle, S. (2017) Mechanisms of drug–drug interaction between rifampicin and fusidic acid. Br J Clin Pharmacol, 83: 1862–1864. doi: 10.1111/bcp.13277.