title: Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice.
abstract: OBJECTIVE
  The pharmacokinetic interaction between metronidazole, an antibiotic-antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P-glycoprotein substrate kinase inhibitor anticancer drug, was evaluated.
  
  
  METHODS
  Male imprinting control region mice were given 50 mg/kg imatinib PO (control group) or 50 mg/kg imatinib PO, 15 min after 40 mg/kg PO metronidazole (study group). Imatinib plasma, brain, kidney and liver concentrations were measured by HPLC and non-compartmental pharmacokinetic parameters estimated.
  
  
  RESULTS
  Metronidazole coadministration resulted in a double-peak imatinib disposition profile. The maximum concentration (C(max)) decreased by 38%, the area under the curve (AUC(0-∞)) decreased by 14% and the time to C(max) (T(max)) was earlier (50%) in plasma. Apparent volume of distribution (V(SS)/F) and oral clearance (Cl/F) increased by 21% and 17%, respectively. Imatinib tissue penetration was higher after metronidazole coadministration, with 1.7 and 2.1-fold AUC(0-∞) increases in liver and kidney, respectively. Metronidazole increased imatinib's tissue-to-plasma AUC(0-∞) ratio in liver from 2.29 to 4.53 and in kidney from 3.04 to 7.57, suggesting higher uptake efficiency. Brain C(max) was 3.9-fold higher than control and AUC(0-t last) was 2.3-fold greater than plasma (3.5% in control group). No tissue-plasma concentration correlation was found.
  
  
  CONCLUSIONS
  Metronidazole slightly decreased imatinib systemic exposure but enhanced liver, kidney and brain penetration, probably due to metronidazole-mediated inhibition of P-glycoprotein and other efflux transporters. The high brain exposure opens possibilities for treatment of glioma and glioblastoma. Renal and hepatic functions may need to be monitored due to potential renal and hepatic toxicity.
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur, Malaysia.
authors.forename: Shin Yee
authors.initials: SY
authors.lastname: Tan
authors.forename: Elaine
authors.initials: E
authors.lastname: Kan
authors.forename: Wei Yin
authors.initials: WY
authors.lastname: Lim
authors.forename: Grace
authors.initials: G
authors.lastname: Chay
authors.forename: Jason H K
authors.initials: JH
authors.lastname: Law
authors.forename: Gian Wan
authors.initials: GW
authors.lastname: Soo
authors.forename: Nadeem Irfan
authors.initials: NI
authors.lastname: Bukhari
authors.forename: Ignacio
authors.initials: I
authors.lastname: Segarra
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000981:Antiprotozoal Agents / Q000009:adverse effects / Q000494:pharmacology*; D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D000068877:Imatinib Mesylate; D008297:Male; D008657:Metabolic Clearance Rate; D008795:Metronidazole / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011897:Random Allocation; D014018:Tissue Distribution
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D008795:Metronidazole; D000068877:Imatinib Mesylate