[Respective role of mifepristone (RU486) binding to blood and tissue proteins in its quantitative distribution in the body].
In plasma, mifepristone (RU486)-alpha 1-glycoprotein acid (AGP) interaction follows a quickly saturable process within the range of therapeutic concentrations. The high affinity to AGP, Kap = 8 x 10(6) M-1, suggests that the tissue distribution of the drug is possibly impaired. Checking this hypothesis was done by simulating its body distribution between plasma proteins and tissues. Two methods were used. The first was to calculate the number of available binding sites in both plasma (Np) and tissues (NT), to measure the relevant association constants Kap and KaT, and to consider that mifepristone partitioned according to their ratios, expressed as [NpKap]/[NpKap + NTKaT] for the plasma and [NTKaT]/ NpKap + NTKaT] for the tissues. The second method used equations relating the apparent volume of distribution and the plasma unbound fraction of mifepristone with volumes of physiologic spaces to calculate the percentage of drug located in plasma, extracellular and intracellular fluids. The results yielded by the two methods are close. They show that with AGP levels within a normal range (18.4 microM), only 18% of mifepristone is bound to AGP and the remaining part 82% is located in tissues. By contrast, when AGP level dramatically increases (300 microM) most of the dose (77%) is retained in plasma. These results suggested that when AGP concentration increases, the efficacy of therapeutic concentration of mifepristone may be partially decreased if only the unbound fraction of this synthetic hormone were biologically active.
Grimaldi
B
B
Département de Pharmacologie, Faculté de Médecine de Créteil.
Barre
J
J
Tillement
J P
JP
D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015735:Mifepristone / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D009961:Orosomucoid / Q000008:administration & dosage / Q000378:metabolism*; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
D009961:Orosomucoid; D011965:Receptors, Glucocorticoid; D015735:Mifepristone
Les rôles respectifs des liaisons aux protéines sanguines et tissulaires de la mifépristone (RU486) dans sa distribution quantitative dans l'organisme.