title: Renal disposition and drug interaction screening of (-)-2'-deoxy-3'-thiacytidine (3TC) in the isolated perfused rat kidney.
abstract: OBJECTIVE
  Dideoxynucleoside bases are used for the treatment of acquired immune deficiency syndrome (AIDS), acting by inhibiting reverse transcriptase and preventing human immunodeficiency virus (HIV) replication. Currently, AZT (zidovudine), ddC (zalcitibine), and ddI (didanosine) are available to the medical community to prevent the onset of AIDS in HIV-infected individuals. 3TC (-)-2'-deoxy-3'-thiacytidine, lamivudine), a new dideoxynucleoside base, is currently undergoing Phase II/III trials, and has exhibited anti-HIV replication activity, a favorable adverse event safety profile, and is eliminated via renal mechanisms. Concomitantly administered drugs could potentiate the effects of 3TC due to interaction in the kidney.
  
  
  METHODS
  An isolated perfused rat kidney (IPK) technique was used to screen several clinically relevant drugs for potential interaction with 3TC. The following perfusions were performed: baseline 3TC; and 500 ng/mL 3TC with clinically relevant concentrations of AZT, ddC, ddI, probenecid, trimethoprim, sulfamethoxazole, ranitidine, and cimetidine.
  
  
  RESULTS
  Renal clearance of 3TC was nonlinear between 500 and 5000 ng/mL, decreasing from 3.06 to 1.74 mL/min. Excretion ratio also decreased, from 3.67 (500 ng/mL) to 2.49 (5000 ng/mL), consistent with a decrease in 3TC secretion. AZT, ddI, and ddC elicited no or minimal effects on 3TC elimination at the concentrations studied. However, trimethoprim caused significant reductions in 3TC elimination parameters: clearance and excretion ratio decreased to 1.25 mL/min and 1.43, respectively.
  
  
  CONCLUSIONS
  These results indicate that caution should be exercised when the combination of 3TC and trimethoprim are administered to AIDS patients.
authors.affiliation: School of Pharmacy, University of Connecticut, Storrs 06269, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Sweeney
authors.forename: P H
authors.initials: PH
authors.lastname: Hsyu
authors.forename: P
authors.initials: P
authors.lastname: Statkevich
authors.forename: D R
authors.initials: DR
authors.lastname: Taft
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007668:Kidney / Q000378:metabolism*; D019259:Lamivudine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D019259:Lamivudine; D016047:Zalcitabine