PHARMACOKINETICS J Clin Pharmacol 2009;49:965-972 965 The pharmacokinetics of cyclophosphamide (CYC) enantiomers were evaluated in patients with lupus nephri- tis distributed in 2 groups according to creatinine clear- ance: 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 ≤ .05) were observed between the (S)-(–) and (R)-(+) enantiomers: AUC 0-∞ 152.41 vs 129.25 µg⋅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-∞ 167.20 vs 139.08 µg⋅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 ≤ .05) were observed between groups 1 and 2 in the pharmacokinetic parameters of both enantiomers. No significant relation- ship 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 param- eters of both enantiomers are not altered by the worsening of renal condition. Keywords: Cyclophosphamide; enantiomers; lupus nephritis; pharmacokinetics; midazolam Journal of Clinical Pharmacology, 2009;49:965-972 © 2009 the American College of Clinical Pharmacology Influence of Glomerular Filtration Rate on the Pharmacokinetics of Cyclophosphamide Enantiomers in Patients With Lupus Nephritis Carolina de Miranda Silva, BSC, Bruno José Dumêt Fernandes, PhD, Eduardo Antônio Donadi, MD, PhD, Lucienir Maria Silva, MD, PhD, Eduardo Barbosa Coelho, MD, PhD, Márcio Dantas, MD, PhD, Maria Paula Marques, PhD, and Vera Lucia Lanchote, PhD From the Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Brazil (de Miranda Silva, Fernandes, Marques, Lanchote) and Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Brazil (Silva, Coelho, Dantas). Submitted for publication December 4, 2008; revised version accepted April 23, 2009. Address for correspondence: Vera Lucia Lanchote, 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; e-mail: lanchote@fcfrp.usp.br. DOI: 10.1177/0091270009337938 N ephritis is a major cause of morbidity in sys- temic lupus erythematosus (SLE) and is pres- ent in one half to two thirds of patients. Controlled randomized studies have shown that intravenous pulse therapy with cyclophosphamide (CYC) is effective for moderate to severe proliferative lupus nephritis. 1 CYC undergoes extensive metabolism to form active (alkylating) and inactive products. Approximately 70% to 80% of the administered dose of CYC is activated by cytochrome P450 (CYP) to form 4-hydroxycyclophosphamide. Various CYP enzymes have been demonstrated to be involved in this reaction, including CYP2A6, CYP2B6, CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP2C19, with CYP2B6 displaying the highest 4-hydroxylase activ- ity. 4-Hydroxycyclophosphamide readily diffuses into cells and spontaneously decomposes into phos- phoramide mustard, which is considered to be the ultimate metabolite responsible for the alkylating effect of CYC. 2 Both the metabolites and a fraction (up to 25%) of unchanged parent compound are elimi- nated by the kidneys. 3 Variations in the balance between metabolic activation and inactivation of CYC owing to drug-drug interactions, genetic factors, and