In vitro influence of fatty acids and bilirubin on binding of mycophenolic acid to human serum albumin.
Mycophenolic acid (MPA) is 98-99% bound to albumin. Because MPA is restrictively cleared and has a low extraction coefficient, increase in its free fraction related to decreased albumin binding results in lower total concentrations but unchanged unbound concentrations. Multiple factors, including hypoalbuminemia, impaired renal function, and accumulated mycophenolic acid glucuronide are known to reduce MPA protein binding. Little is known about the influence of fatty acids and bilirubin on this issue. By using quenching fluorescence method, the aims of this study were to investigate in vitro the binding properties of MPA, then the influence of myristic acid and bilirubin on MPA binding to albumin. The estimate of dissociation constant (Kd) of MPA was 13.2 [CI 95 12.7-13.8] μM. In the presence of myristic acid (concentration range 4-100 μM), apparent Kd (Kd(app)) of MPA was approximately 1.5-10-fold greater. For myristic acid/albumin molar ratio reachable in clinical settings (2:1 and 5:1), Kd(app) of MPA rose about a factor 1.5 and 2.2, respectively. In the presence of bilirubin (concentration range 0.5-5 μM), Kd(app) of MPA was approximately 1.5-5-fold greater than MPA Kd. For bilirubin/albumin molar ratio reachable in clinical settings (1:4 and 1:2), Kd(app) of MPA rose about a factor 1.5 and 1.9, respectively. These data suggest that hypertriglyceridemia or cholestasis may significantly increase MPA free fraction in clinical settings, thereby lowering MPA total concentration in plasma while the free concentration remains unchanged. These results may help to optimize the therapeutic drug monitoring of MPA.
Laboratoire de pharmacologie-toxicologie, service de Pharmacie, GH Cochin Saint Vincent de Paul, 75014 Paris, APHP, France.
Yoann
Y
Vial
Michel
M
Tod
Marilyne
M
Hornecker
Saik
S
Urien
Filomena
F
Conti
Alain
A
Dauphin
Yvon
Y
Calmus
Benoit
B
Blanchet
D001663:Bilirubin / Q000378:metabolism*; D016903:Drug Monitoring; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D009173:Mycophenolic Acid / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D019814:Myristic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*
D005227:Fatty Acids; D007166:Immunosuppressive Agents; D012709:Serum Albumin; D019814:Myristic Acid; D009173:Mycophenolic Acid; D001663:Bilirubin