Comparative preclinical drug metabolism and pharmacokinetic evaluation of novel 4-aminoquinoline anti-malarials.
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 approximately 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 ( approximately 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.
Davis
Charles B
CB
Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Drug Discovery, 1250 South Collegeville Rd, Collegeville, Pennsylvania 19426, USA. charles.b.davis@gsk.com
Bambal
Ramesh
R
Moorthy
Ganesh S
GS
Hugger
Erin
E
Xiang
Hong
H
Park
Brian Kevin
BK
Shone
Allison E
AE
O'Neill
Paul M
PM
Ward
Stephen A
SA
D000634:Aminoquinolines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000634:Aminoquinolines; D000962:Antimalarials; C001920:4-aminoquinoline