title: Gender-associated differences in rat renal tubular amantadine transport and absence of stereoselective transport inhibition by quinine and quinidine in distal tubules.
abstract: The present studies compared male and female rat renal proximal and distal tubular uptake of amantadine, in relation to their transport kinetics and enantioselective inhibition by two diastereoisomers, 8S,9R-(-)-quinine and 8R,9S-(+)-quinidine. Under control conditions, amantadine was concentrated by both tubule fractions with a gender difference for distal tubules (tissue:medium ratio, 18.0 +/- 1.4 for males and 11.0 +/- 0.6 for females; mean +/- S.E.M., P < .05). This was reflected by a higher Km value only in female distal vs. proximal tubular tissue (153 +/- 8 vs. 108 +/- 9 microM; P < .01) but decrease in Vmax values in distal compared to proximal tubules (P < .01) showed no gender-related difference. In proximal tubules, 8S,9R-(-)-quinine and 8R,9S-(+)-quinidine competitively inhibited amantadine transport with apparent inhibitory potency of 2- to 3-fold in favor of 8S,9R-(-)-quinine (P < .01) and without gender preference. Conversely in distal tubules, competitive inhibition of amantadine transport was also elicited by either 8S,9R-(-)-quinine or 8R,9S-(+)-quinidine at a similar concentration range (10-1000 microM), with absence of chiral or gender preference. The present transport data have demonstrated an apparent absence of stereoselectivity in distal tubular uptake inhibition of amantadine, and are suggestive of disparate pathways and/or rate limiting steps involved between renal proximal and distal tubular handling of chiral organic cations for both genders, and between genders for distal tubular transport of amantadine.
authors.affiliation: Department of Pharmacology, University of Manitoba, Winnipeg, Canada.
authors.forename: L T
authors.initials: LT
authors.lastname: Wong
authors.forename: M R
authors.initials: MR
authors.lastname: Escobar
authors.forename: D D
authors.initials: DD
authors.lastname: Smyth
authors.forename: D S
authors.initials: DS
authors.lastname: Sitar
mesh_terms: D000547:Amantadine / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D005260:Female; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D011802:Quinidine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D013237:Stereoisomerism
chemical_list: D011803:Quinine; D000547:Amantadine; D011802:Quinidine