In vitro pharmacokinetics of anti-psoriatic fumaric acid esters.
BACKGROUND
Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments.


RESULTS
DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.


CONCLUSIONS
Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.
Litjens
Nicolle H R
NH
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. nicollelitjens@hotmail.com
van Strijen
Elisabeth
E
van Gulpen
Co
C
Mattie
Herman
H
van Dissel
Jaap T
JT
Thio
H Bing
HB
Nibbering
Peter H
PH
D001773:Blood Cells / Q000378:metabolism; D002021:Buffers; D003879:Dermatologic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000069462:Dimethyl Fumarate; D004355:Drug Stability; D004952:Esters / Q000378:metabolism; D005650:Fumarates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D066298:In Vitro Techniques; D007421:Intestine, Small; D008298:Maleates / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy; D044967:Serum / Q000378:metabolism; D013270:Stomach
D002021:Buffers; D003879:Dermatologic Agents; D004952:Esters; D005650:Fumarates; D008298:Maleates; C073341:citraconic acid; D000069462:Dimethyl Fumarate; C061175:ethyl fumarate