title: Interference with renal organic cation transport by (-)- and (+)-nicotine at concentrations documented in plasma of habitual tobacco smokers.
abstract: Nicotine is the principal psychoactive Nicotiana alkaloid in tobacco. In the present study, we used amantadine as a marker and investigated the potential ability of nicotine and cotinine to interfere with renal organic cation transport in vitro. [3H]Amantadine is concentrated actively by isolated proximal tubules, distal tubules and cortical slices. In proximal tubules, the addition of (-)- or (+)-nicotine (0.1-100 microM) facilitated amantadine (10 microM) accumulation. Apparent Km for amantadine uptake was decreased by a clinically relevant concentration of (-)- and (+)-nicotine (0.4 microM), from 78 +/- 2 to 52 +/- 2 and 61 +/- 5 microM, respectively (mean +/- S.E.M., P less than .05), whereas Vmax was not altered (6.6 +/- 0.1 to 6.3 +/- 0.1 and 6.5 +/- 0.2 nmol/mg/min). The addition of (-)-cotinine (0.4-100 microM) also facilitated amantadine uptake, but with lesser efficacy. Possible mechanisms underlying the present enhancement of uptake include facilitation of amantadine influx and/or attenuation of efflux. Efflux data indicate a prominent hindrance of amantadine egress from preloaded tubules in the presence of 0.4 microM (-)- and (+)-nicotine (51 +/- 4 to 32 +/- 8 and 27 +/- 4 pmol/mg/30 sec, P less than .05) and are supportive of the latter notion. In distal tubules, (-)- or (+)-nicotine produced inhibition only a high concentrations (greater than or equal to 100 microM). Km was increased by 400 microM (-)- and (+)-nicotine from 76 +/- 5 to 124 +/- 9 and 116 +/- 17 microM, and Vmax was moderately decreased from 3.4 +/- 0.5 to 3.0 +/- 0.4 and 3.0 +/- 0.4 nmol/mg/min (P less than .05). The incorporation of (-)-cotinine did not alter amantadine uptake. Enhancement of uptake by (-)- or (+)-nicotine was absent in cortical slices, in which tubular luminal transport has ben proposed to be insignificant, and only low affinity inhibition was apparent. The present data indicate potent interference of renal proximal tubular transport of amantadine by nicotine at concentrations equivalent to those documented in plasma of habitual tobacco smokers and suggest potential alterations in renal organic cationic drug elimination in these subjects.
authors.affiliation: Department of Pharmacology, University of Manitoba, Winnipeg, Canada.
authors.forename: L T
authors.initials: LT
authors.lastname: Wong
authors.forename: D D
authors.initials: DD
authors.lastname: Smyth
authors.forename: D S
authors.initials: DS
authors.lastname: Sitar
mesh_terms: D000547:Amantadine / Q000378:metabolism*; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003367:Cotinine / Q000494:pharmacology; D006801:Humans; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012907:Smoking / Q000097:blood; D013237:Stereoisomerism
chemical_list: D009538:Nicotine; D002927:Cimetidine; D000547:Amantadine; D003367:Cotinine