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Comparative Preclinical Drug Metabolism and Pharmacokinetic Evaluation of Novel 4-Aminoquinoline Anti-Malarials

Davis, C. B., Bambal, R., Moorthy, G. S., Hugger, E., Xiang, H., Park, R. K., Shone, Alison, O'Neill, P. M. and Ward, Stephen ORCID: (2009) 'Comparative Preclinical Drug Metabolism and Pharmacokinetic Evaluation of Novel 4-Aminoquinoline Anti-Malarials'. Journal of Pharmaceutical Sciences, Vol 98, Issue 1, pp. 362-377.

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The disposition of three 4-aminoquinoline leads, namely isoquine (ISO), des-ethyl isoquine (DEI) and N-tert-butyl isoquine (NTBI), were studied in a range of in vivo and in vitro assays to assist in selecting an appropriate candidate for further development. Analogous to amodiaquine (ADQ), ISO undergoes oxidative N-dealkylation to form DEI in vivo. Blood clearance of DEI was as much as 10-fold lower than that of ISO in animals and after oral administration, metabolite exposure exceeded that of parent by as much as 14-fold. Replacement of the N-ethyl with an N-tert-butyl substituent substantially reduced N-dealkylation as blood clearance of NTBI was similar to 2 to 3-fold lower than DEI in mouse, rat, dog and monkey. Mean NTBI oral bioavailability was generally higher than the other leads (>= 68%). Blood cell association was substantial for NTBI, particularly in dog and monkey, where blood to plasma concentration ratios >4 were observed. Human plasma protein binding was similar for NTBI, DEI, and des-ethyl amodiaquine (DEA). Allometric scaling predicted human blood clearance (CL) for NTBI to be low (similar to 12% liver blood flow). All the 4-aminoquinolines inhibited recombinant human cytochrome P450 2D6 with similar potency; DEI also inhibited 1A2. On balance, NTBI appeared the most promising lead to progress towards full development. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:362-377, 2009

Item Type: Article
Uncontrolled Keywords: preclinical pharmacokinetics drug design pro-drugs adme cytochrome p450 mdck cells protein binding blood partitioning anti-malarials bioactivation plasmodium-falciparum in-vitro liquid-chromatography high-affinity amodiaquine chloroquine agranulocytosis parameters cyp2c8 assays
Subjects: WB Practice of Medicine > WB 25 Technique of research in internal medicine
QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs
QX Parasitology > Protozoa > QX 135 Plasmodia
QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):
Depositing User: Mary Creegan
Date Deposited: 22 Jun 2010 10:24
Last Modified: 17 Jul 2020 10:56


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