Antimicrob Agents Chemother. 2014 Jun;58(6):3168-76. doi: 10.1128/AAC.02278-13.

Comparative study of the effects of anti-tuberculosis drugs and antiretroviral drugs on CYP3A4 and P-glycoprotein

 

Horita Y and Doi N

Department of Pathophysiology and Host Defense, Japan Anti-Tuberculosis Association, Research Institute of Tuberculosis, 3-1-24 Matsuyama, Kiyose, Tokyo 204-8533, Japan

 

ABSTRACT

Predicting drug-drug interactions (DDIs) related to cytochrome P450 (CYP) such as CYP3A4 and one of the major drug transporters, P-glycoprotein (P-gp), is crucial for the development of future chemotherapeutic regimens to treat tuberculosis (TB) and TB/AIDS co-infection cases1. We evaluated the effects of 30 anti-TB drugs, novel candidates, macrolides, and representative antiretroviral drugs on human CYP3A4 activity using a commercially available screening kit for CYP3A4 inhibitors and a human hepatocyte, HepaRG. Moreover, in order to estimate the interactions of these drugs with human P-gp, screening for substrates was performed. For some substrates, P-gp inhibition tests were carried out using P-gp-expressing MDCK cells. As a result, almost all the compounds showed the expected effects on human CYP3A4 both in the in vitro screening and HepaRG cells. Importantly, the unproved mechanisms of DDIs caused by WHO group-five drugs, thioamides, and p-aminosalicylic acid were elucidated. Intriguingly, CFZ exhibited weak inductive effects on CYP3A4 at more than 0.25 μM in HepaRG, while the inhibitory effect was observed at 1.69 μM in the in vitro screening, suggesting that CFZ autoinduces CYP3A4 in the human liver. Our method based on one of the pharmacokinetics parameters in humans provides more practical information associated with not only DDIs but also drug metabolism.

PMID: 24663015

 

SUPPLEMENTARY

HepaRG is useful for estimating the inductive and/or inhibitory effects of drugs and chemicals on CYP3A4 activity2. The principal of our main research is depicted as follows. We comprehensively determined unknown and controversial DDIs of anti-TB drugs related to CYP3A4 and P-gp. Whereas the ex vivo study itself is inconclusive, it sheds light on the pathway for developing safety regimens for the treatment of TB, MAC, and AIDS. When officially determining a suitable dose in humans, the effects of pharmaceutical drugs on drug-metabolizing enzymes and membrane transporters which are likely to be the causative factors involved in DDIs should be re-evaluated at clinically achievable concentrations.

 

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REFERENCES

  1. Kwara, A., G. Ramachandran, and S. Swaminathan. 2010. Dose adjustment of the non-nucleoside reverse transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not fit all. Expert Opin Drug Metab Toxicol 6:55-68.
  2. Antherieu, S., C. Chesne, R. Li, S. Camus, A. Lahoz, L. Picazo, M. Turpeinen, A. Tolonen, J. Uusitalo, C. Guguen-Guillouzo, and A. Guillouzo. 2010. Stable expression, activity, and inducibility of cytochromes P450 in differentiated HepaRG cells. Drug metabolism and disposition: the biological fate of chemicals 38:516-525.

 

CONTACT

Norio DOI, PhD.

Department of Pathophysiology and Host Defense, Japan Anti-Tuberculosis Association, Research Institute of Tuberculosis, 3-1-24 Matsuyama, Kiyose, Tokyo 204-8533, Japan.

Phone: +81-42-493-5711. E-mail: ndoi@jata.or.jp.

 

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