Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice.
Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib's protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)--> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)-->infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)-->infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib's distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring.
Soo
Gian Wan
GW
Department of Pharmaceutical Technology, International Medical University, Kuala Lumpur, Malaysia.
Law
Jason H K
JH
Kan
Elaine
E
Tan
Shin Yee
SY
Lim
Wei Yin
WY
Chay
Grace
G
Bukhari
Nadeem I
NI
Segarra
Ignacio
I
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001549:Benzamides; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000068877:Imatinib Mesylate; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010879:Piperazines / Q000493:pharmacokinetics*; D011319:Primaquine / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects
D000935:Antifungal Agents; D000962:Antimalarials; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011319:Primaquine; D007654:Ketoconazole