Influence of glomerular filtration rate on the pharmacokinetics of cyclophosphamide enantiomers in patients with lupus nephritis.
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.
de Miranda Silva
Carolina
C
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.
Fernandes
Bruno José Dumêt
BJ
Donadi
Eduardo Antônio
EA
Silva
Lucienir Maria
LM
Coelho
Eduardo Barbosa
EB
Dantas
Márcio
M
Marques
Maria Paula
MP
Lanchote
Vera Lucia
VL
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
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D003404:Creatinine; D008874:Midazolam