Evaluation of Interleukin-2 mRNA in Whole Blood as a Parameter for Monitoring Cyclosporine Pharmacodynamics

• Published in: Biological & Pharmaceutical Bulletin Vol. 32; no. 4; pp. 604 - 608
• Main Authors: Kuzuya, Takafumi, Uchida, Kazuharu, Yamada, Kiyofumi, Nagasaka, Takaharu, Kobayashi, Takaaki, Miwa, Yuko, Nakao, Akimasa, Katayama, Akio
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.04.2009; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Adult; Aged; Algorithms; Anti-Inflammatory Agents - pharmacology; cyclosporine; Cyclosporine - pharmacokinetics; Cyclosporine - pharmacology; Drug Monitoring; Female; Humans; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - pharmacology; interleukin-2; Interleukin-2 - biosynthesis; Kidney Transplantation - immunology; Male; Middle Aged; pharmacodynamics; Prednisolone - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - blood; Young Adult
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.32.604

Inhibition of cytokine production is the main immunosuppressive effect of cyclosporine (CsA), which is widely used in organ transplantation. Pharmacodynamic (PD) assay for evaluating the inhibition of interleukin-2 (IL-2) production for each patient could provide a more appropriate dosing regimen. We measured the suppression of IL-2 mRNA expression in whole blood following the addition of a range of CsA concentrations by a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Individual CsA sensitivity on the IL-2 mRNA expression was assessed with healthy subjects both in vitro and ex vivo. We also evaluated it in pre-transplant patients before taking immunosuppressive drugs. Sigmoid Emax model was used to analyze the relationship between CsA concentration and IL-2 mRNA expression. The assay was completed within 8 h. The concentration that resulted in IC50 showed high reproducibility and specificity among the healthy subjects (p<0.005, n=5). Ex vivo study indicated similar inhibition profiles to those of in vitro studies (n=3). The values of IC50 obtained from patients (n=22) also showed large variations and were significantly lower than those from healthy subjects (p<0.05). Semi-quantitative RT-PCR was considered to be a rapid and reliable assay. Our data imply that measurement of IL-2 mRNA levels in whole blood could be valuable in monitoring CsA PD in transplant patients.