Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis.

Abstract

The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose. Cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide enantiomers were analyzed in plasma samples using liquid chromatography-tandem mass spectrometry coupled to chiral column Chiralcel OD-R or Chiralpak AD-RH. Cytokines IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p70, IL-17, TNF-α, and INT-δ in the plasma samples collected before cyclophosphamide infusion were analyzed by Milliplex MAP human cytokine/chemokine. Pharmacokinetic parameters showed higher plasma concentrations of (S)-(-)-cyclophosphamide (AUC 215.0 vs 186.2 μg·h/mL for multiple sclerosis patients and 219.1 vs 179.2 μg·h/mL for systemic sclerosis patients) and (R)-4-hydroxycyclophosphamide (AUC 5.6 vs 3.7 μg·h/mL for multiple sclerosis patients and 6.3 vs 5.6 μg·h/mL for systemic sclerosis patients) when compared to their enantiomers in both groups of patients, whereas the pharmacokinetics of the carboxyethylphosphoramide metabolite was not enantioselective. Cytokines' plasma concentrations were similar between multiple and systemic sclerosis groups. The pharmacokinetics of cyclophosphamide is enantioselective in patients with systemic sclerosis and multiple sclerosis, with higher plasma concentrations of the (S)-(-)-cyclophosphamide enantiomer due to the preferential formation of the (R)-4-hydroxycyclophosphamide metabolite.

• Authors: Francine Attié de Castro, Belinda Pinto Simões, Eduardo Barbosa Coelho, Vera Lucia Lanchote
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 57 Issue 6 Pg. 784-795 (06 2017) ISSN: 1552-4604 [Electronic] England
• PMID: 28083951 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017, The American College of Clinical Pharmacology.

Chemical References

• Cytokines
• Immunosuppressive Agents
• Cyclophosphamide
• CYP2C9 protein, human
• Cytochrome P-450 CYP2C9
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6

Topics

• Adult
• Cyclophosphamide (analogs & derivatives, blood, pharmacokinetics, pharmacology)
• Cytochrome P-450 CYP2B6 (genetics)
• Cytochrome P-450 CYP2C9 (genetics)
• Cytokines (blood)
• Female
• Genotype
• Humans
• Immunosuppressive Agents (blood, pharmacokinetics, pharmacology)
• Male
• Middle Aged
• Multiple Sclerosis (blood, genetics, metabolism)
• Scleroderma, Systemic (blood, genetics, metabolism)
• Stereoisomerism