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P-glycoprotein-dependent pharmacokinetics of irinotecan and its active metabolite, SN-38 in rats: Effect of verapamil

Tripta Garg ; Full Affiliation, Address 1Department of Scientific and Industrial Research, Ministry of Science and Technology, New Mehrauli Road, New Delhi 110016, India
Manu Jagg ; Dabur Research Foundation, 22, Site IV, Sahibabad, Ghaziabad, U.P. 201010, India
Roop K. Khar ; Principal, B. S. Anangpuria Institute of Pharmacy, Faridabad, India
Sushama Talegaonkar ; Dept. of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard (Hamdard University, Hamdard Nagar, New Delhi 110062, India

Puni tekst: engleski pdf 844 Kb

str. 68-76

preuzimanja: 820



We have recently demonstrated that the oral bioavailability of irinotecan (80 mg/kg) can be increased at least 7-fold by co-administration of the P-gp blocker verapamil (25 mg/kg, Oral). As a result, co-treatment with P-gp inhibitor could be a useful strategy for bioavailability enhancement. However, in view of narrow therapeutic index, the co-administration of irinotecan and verapamil may result in unanticipated toxicities. Therefore, dose optimisation studies of irinotecan were performed when it is given in conjunction with a P-gp inhibitor. For dose optimization study, the bioavailability and pharmacokinetic parameters were studied in rats after oral administration of irinotecan at three doses (i.e. 20, 40 and 80 mg/kg) alone and in combination with verapamil (25 mg/kg, oral). The area under the plasma-concentration time curve (AUC) of irinotecan at 20, 40 and 80 mg/kg was 3.51 ± 1.20, 8.81 ± 1.93 and 14.03 ± 2.18 h µg/ml, respectively which after treatment with verapamil, increased dose dependently to 7.84 ± 1.20, 19.94 ± 2.39 and 61.71 ± 15.0 h µg/ml, respectively. In addition to irinotecan, plasma concentrations of SN-38, one of the major active metabolite of irinotecan, were also monitored. The less than proportional increase in SN-38 AUC from 20 to 80 mg/kg is consistent with the saturation of carboxylesterase. Our results indicate that oral drug treatment of irinotecan in presence of temporary P-gp inhibition could be as equally safe and effective as intravenous administration. Nevertheless, safe P-gp inhibitors need to be identified as alternatives to verapamil for development of efficacious oral irinotecan formulations.

Ključne riječi

Irinotecan; bioavailability; verapamil; P-glycoprotein; pharmacokinetics

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