In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data.
Formononetin (FMN) and Biochanin A (BCA) are the principal isoflavones present in commercially available extracts of red clover that are widely been consumed for various health benefits. We investigated the in vitro effects of FMN and BCA on catalytic activity of human/rat cytochrome P450 enzymes to assess the drug interaction potential of red clover. IC50 and Ki values of FMN and BCA for CYPs were determined in human/rat liver microsomes. FMN and BCA showed concentration-dependent inhibition of CYP1A2 activity with IC50 values of 13.42 and 24.98μM in human liver microsomes and 38.57 and 11.86μM in rat liver microsomes, respectively. The mode of inhibition of human CYP1A2 by FMN was found to be competitive with apparent Ki value of 10.13±1.96μM. FMN also inhibited human CYP2D6. BCA exerted moderately inhibitory effects on human CYP2C9. The predicted in vivo inhibition for CYP1A2 was insignificant (R value <1.1) at hepatic level while at intestinal level, it was significant (R value >11). The inhibitory effects on other CYPs were found to be minimal. Red clover may be considered safe to be consumed along with co-prescribed medications; however, precaution must be taken while co-administering it with CYP1A2 substrates.
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
Sumit
S
Arora
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi, India.
Isha
I
Taneja
National Institute of Pharmaceutical Research and Education, Raebareli, India.
Muralikrishna
M
Challagundla
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi, India.
Kanumuri Siva Rama
KS
Raju
Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India. Electronic address: sheelendra@iitr.res.in.
Sheelendra Pratap
SP
Singh
Pharmacokinetics and Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India; Academy of Scientific and Innovative Research, New Delhi, India; National Institute of Pharmaceutical Research and Education, Raebareli, India. Electronic address: wahajuddin@cdri.res.in.
Muhammad
M
Wahajuddin
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004347:Drug Interactions; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D029921:Trifolium / Q000009:adverse effects / Q000737:chemistry
D065607:Cytochrome P-450 Enzyme Inhibitors; D007529:Isoflavones; C007768:formononetin; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein; C004541:biochanin A
Cytochrome P450; Enzyme inhibition; Herb–drug interaction; Isoflavones; liver microsomes