Skip to Content
MilliporeSigma
  • Metabolic drug-drug interaction potential of macrolactin A and 7-O-succinyl macrolactin A assessed by evaluating cytochrome P450 inhibition and induction and UDP-glucuronosyltransferase inhibition in vitro.

Metabolic drug-drug interaction potential of macrolactin A and 7-O-succinyl macrolactin A assessed by evaluating cytochrome P450 inhibition and induction and UDP-glucuronosyltransferase inhibition in vitro.

Antimicrobial agents and chemotherapy (2014-06-04)
Soo Hyeon Bae, Min Jo Kwon, Jung Bae Park, Doyun Kim, Dong-Hee Kim, Jae-Seon Kang, Chun-Gyu Kim, Euichaul Oh, Soo Kyung Bae
ABSTRACT

Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice.

MATERIALS
Product Number
Brand
Product Description

Supelco
Chlorpropamide, analytical standard, ≥97%
Sigma-Aldrich
Uridine 5′-diphosphoglucuronic acid ammonium salt, 98-100%
Supelco
Umbelliferone, analytical standard
Supelco
Dimethyl sulfoxide, analytical standard
Phenytoin for system suitability, European Pharmacopoeia (EP) Reference Standard
USP
Trifluoperazine hydrochloride, United States Pharmacopeia (USP) Reference Standard
Zidovudine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Dimethyl sulfoxide, Vetec, reagent grade, 99%
USP
Methyl alcohol, United States Pharmacopeia (USP) Reference Standard
Supelco
Methanol solution, contains 0.10 % (v/v) formic acid, UHPLC, suitable for mass spectrometry (MS), ≥99.5%
Supelco
L-Glutamine, certified reference material, TraceCERT®, Manufactured by: Sigma-Aldrich Production GmbH, Switzerland
Sigma-Aldrich
Methanol solution, NMR reference standard, 4% in methanol-d4 (99.8 atom % D), NMR tube size 3 mm × 8 in.
Sigma-Aldrich
Formic acid, ACS reagent, ≥96%
Niflumic acid, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Formic acid, puriss., meets analytical specifications of DAC, FCC, 98.0-100%
Sigma-Aldrich
Formic acid, reagent grade, ≥95%
Sigma-Aldrich
Dimethyl sulfoxide, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Formic acid, puriss. p.a., ACS reagent, reag. Ph. Eur., ≥98%
Sigma-Aldrich
Dimethyl sulfoxide, puriss. p.a., dried, ≤0.02% water
Sigma-Aldrich
Dimethyl sulfoxide, ACS reagent, ≥99.9%
Sigma-Aldrich
Dimethyl sulfoxide, suitable for HPLC, ≥99.7%
Sigma-Aldrich
Dimethyl sulfoxide, puriss. p.a., ACS reagent, ≥99.9% (GC)
Sigma-Aldrich
Formic acid, ACS reagent, ≥88%
Supelco
Dimethyl sulfoxide, for inorganic trace analysis, ≥99.99995% (metals basis)
USP
Zidovudine, United States Pharmacopeia (USP) Reference Standard
Dimethyl sulfoxide, European Pharmacopoeia (EP) Reference Standard
Supelco
Acetaminophen, Pharmaceutical Secondary Standard; Certified Reference Material
Propofol for peak identification, European Pharmacopoeia (EP) Reference Standard
Supelco
Zidovudine, Pharmaceutical Secondary Standard; Certified Reference Material
Chlorpropamide, European Pharmacopoeia (EP) Reference Standard