title: Influence of glomerular filtration rate on the pharmacokinetics of cyclophosphamide enantiomers in patients with lupus nephritis.
abstract: The pharmacokinetics of cyclophosphamide (CYC) enantiomers were evaluated in patients with lupus nephritis distributed in 2 groups according to creatinine clearance: group 1 (90.6-144.6 mL/min/1.73 m(2)) and group 2 (42.8-76.4 mL/min/1.73 m(2)). All patients were treated with 0.75 to 1.3 g of racemic CYC as a 2-hour infusion and with 1 mg intravenous midazolam as a drug-metabolizing marker. CYC enantiomers and midazolam concentrations in plasma were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS). The following differences (Wilcoxon test, P < or = .05) were observed between the (S)-(-) and (R)-(+) enantiomers: AUC(0-infinity) 152.41 vs 129.25 microg.h/mL, CL 3.28 vs 3.89 L/h, Vd 31.38 vs 29.74 L, and t((1/2)) 6.79 vs 5.56 h for group 1 and AUC(0-infinity) 167.20 vs 139.08 microg.h/mL, CL 2.99 vs 3.59 L/h, and t((1/2)) 6.15 vs 4.99 h for group 2. No differences (Mann test, P < or = .05) were observed between groups 1 and 2 in the pharmacokinetic parameters of both enantiomers. No significant relationship was observed between midazolam clearance (2.92-16.40 mL/min.kg) and clearance of each CYC enantiomer. In conclusion, CYC kinetic disposition is enantioselective, resulting in higher exposures of the (S)-(-) enantiomer in lupus nephritis patients, and the pharmacokinetic parameters of both enantiomers are not altered by the worsening of renal condition.
authors: Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Avenida do Café s/n, Campus da USP, 14040-903, Ribeirão Preto, SP, Brazil.
authors: Carolina
authors: C
authors: de Miranda Silva
authors: Bruno José Dumêt
authors: BJ
authors: Fernandes
authors: Eduardo Antônio
authors: EA
authors: Donadi
authors: Lucienir Maria
authors: LM
authors: Silva
authors: Eduardo Barbosa
authors: EB
authors: Coelho
authors: Márcio
authors: M
authors: Dantas
authors: Maria Paula
authors: MP
authors: Marques
authors: Vera Lucia
authors: VL
authors: Lanchote
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002853:Chromatography, Liquid / Q000379:methods; D003404:Creatinine / Q000097:blood / Q000652:urine; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D018709:Statistics, Nonparametric; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D003404:Creatinine; D008874:Midazolam