Showing papers on "Mycophenolate published in 1995"

Mycophenolic acid binding to human serum albumin: characterization and relation to pharmacodynamics.

Abstract: Mycophenolate mofetil, the prodrug form of the immunosuppressive agent mycophenolic acid (MPA), is currently in clinical trials evaluating its effectiveness in transplant recipients. In this study, we validated an ultrafiltration system for the reliable measurement of free MPA. Using this technique, we evaluated factors that might be important in modulating the free fraction of this drug. Human serum albumin (HSA), high concentrations of the primary glucuronide metabolite of MPA, and sodium salicylate significantly affected MPA binding. For HSA the mean +/- SE binding capacity (Bmax) and the dissociation constant (Kd) were 1095 +/- 34 mumol/L and 12.98 +/- 0.93 mumol/L, respectively. The dose for 50% inhibition (IC50) of inosine monophosphate dehydrogenase isoform II by MPA increased 5.4-fold as the concentration of HSA added to the enzyme reaction mixture increased from 0 to 50 g/L (0-724 mumol/L). Furthermore, the IC50 MPA concentration for phytohemagglutinin A-stimulated human peripheral blood mononuclear cells increased 4.8-fold when incubations were performed in the presence of 10 g/L (145 mumol/L) HSA vs no added HSA. These data support the hypothesis that the pharmacological activity of MPA is a function of unbound drug concentration.

Mechanism of action of mycophenolate mofetil

Abstract: Mycophenolate mofetil is a prodrug which is rapidly converted to mycophenolic acid (MPA), a potent and reversible uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH). In the de novo purine synthesis pathway, IMPDH is the first of two enzymes responsible for the conversion of inosine monophosphate (IMP) to guanosine monophosphate (GMP), which is normally converted to GDP, GTP, and dGTP. IMPDH is not involved in the salvage pathway of purine biosynthesis. It has been proposed that, since lymphocytes are relatively independent of the salvage pathway of nucleotide biosynthesis, MPA treatment should reduce guanine nucleotide pools in lymphocytes. Measurements show that MPA causes a reduction of GTP and dGTP in lymphocytes but not neutrophils. The consequences of the reduction in guanine nucleotides in lymphocytes, such as the inhibition of DNA synthesis, and GTP-dependent metabolic events, is discussed.

Mechanisms of action of new immunosuppressive drugs.

Abstract: More immunosuppressive drugs than ever have recently graduated from the laboratory to extensive clinical trials of their safety and efficacy in transplant patients. None of these drugs is perfect, but they control different forms of rejection in stringent animal models more effectively than other immunosuppressants, and these novel molecules suppress the immune system far more specifically than steroids and regimens that cause lymphopenia. Cyclosporin A and FK506 are the only drugs that selectively inhibit T-cell proliferation by blocking cytokine synthesis. The primary action of rapamycin appears to be inhibition of the actions of cytokines and growth factors on T, B, and some nonimmune cells. T and B cells are more sensitive than nonimmune cells to the depletion of purines and pyrimidines caused by mizoribine, mycophenolate mofetil, brequinar sodium, and leflunomide. Nucleotide depletion causes interruption of DNA synthesis and glycosylation of adhesion molecules in immune cells. Further differentiation of T and B cells after proliferation into fully functional immune cells is inhibited by unknown mechanisms of brequinar and deoxyspergualin. On the basis of preclinical studies, these drugs may effectively suppress clinical rejection that is acute (all), chronic (rapamycin, leflunomide, mycophenolate mofetil), or antibody mediated (brequinar, deoxyspergualin, mycophenolate mofetil, rapamycin, leflunomide). Some drugs (FK506, deoxyspergualin, mycophenolate mofetil, rapamycin, leflunomide) may reverse acute rejection refractory to conventional immunosuppression. Not only do these new drugs block different biochemical steps that normally lead to fully functional T and B cells after stimulation by alloantigen, but their toxicity profiles also differ. Results from preclinical studies predict that use of selected combinations of these drugs will be more effective, less nephrotoxic, less myelotoxic, and less broadly immunosuppressive than current regimens based on cyclosporine, T-cell depletion, steroids, and azathioprine.

Mycophenolic acid: measurement and relationship to pharmacologic effects.

Abstract: Validated high-performance liquid chromatographic (HPLC) methods have been developed for the reliable measurement in plasma of mycophenolate mofetil (MMF), mycophenolic acid (MPA), its pharmacologically active metabolite, and mycophenolic acid glucuronide (MPAG), the inactive and primary metabolite of MPA. Using these validated HPLC methods, the pharmacokinetic behavior of MMF has been characterized in renal transplant patients as part of double-blind randomized multicenter clinical trials. The analytical performance characteristics of the HPLC methods are described. Based on investigations of the metabolism of MMF in animals, normal volunteers, and renal transplant patients, it has been established that MMF is rapidly converted to MPA. MPAG is the primary urinary excretion product derived from MPA. In vitro binding studies have revealed that MPA is extensively bound to plasma proteins and that human serum albumin is the primary binding protein. Pharmacokinetic studies have revealed the following: (1) MPA exhibits enterohepatic circulation in humans as a result of biliary excretion of MPAG followed by MPA production in the gastrointestinal tract and the appearance of secondary MPA peaks in plasma; (2) chronic renal impairment produces little change in the clearance of MPA but a marked decrease in plasma MPAG clearance, with a consequent substantial increase in the circulating MPAG concentration; and (3) pharmacokinetic/pharmacodynamic (PK/PD) studies have revealed a good correlation between drug exposure (AUC) and the probability of rejection. The implications of the PK/PD studies for the development of TDM practices are discussed.

5-substituted derivatives of mycophenolic acid

Abstract: The disclosed hexenoic acid side-chain derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil, including immune, inflammatory, tumor, proliferative, viral or psoriatic disorders.

Stability and pharmacokinetic studies of a new immunosuppressant, mycophenolate mofetil (RS-61443), in rats

Abstract: Mycophenolate mofetil (MPM), a new immunosuppressant, is a morpholinoethyl ester of mycophenolic acid (MPA) The enzymatic and non-enzymatic hydrolysis was studied in an artificial digestive fluid, rat plasma, and tissue homogenates MPM was chemically stable in the artificial digestive fluid In rat tissue homogenates and plasma, MPM was rapidly hydrolysed to MPA The conversion rate of MPM to MPA in various rat tissue homogenates was in the order of liver > kidney > plasma > small-intestine epithelial cells After the intravenous injection of MPM at 167 mg kg-1, the terminal elimination half-life, t1/2 beta, was 474 +/- 033 (mean +/- SD)h, and the area under the plasma concentration versus time curve, AUC, was 4878 +/- 601 micrograms h mL-1 After intraduodenal (ID) administration of MPM at 167 mg kg-1, t1/2 beta was 392 +/- 105 h, and the AUC was 3808 +/- 830 micrograms h mL-1 The systemic availability of MPA after ID MPM dosing was 152 times higher than that after ID administration of MPA This result supports the usefulness of MPM as an oral prodrug of MPA as a new oral immunosuppressant

4-amino derivatives of 5-substituted mycophenolic acid

Abstract: The disclosed derivatives of mycophenolic acid of formula (IE) are therapeutic agens advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents. In said formula, Z is a side chain selected from formulae (ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH).

4-amino 6-substituted mycophenolic acid and derivatives

Abstract: The disclosed derivatives of my-cophenolic acid of formula (I) are thera-peutic agents advantageous in the treatment of disease states indicated for mycopheno-lic acid and/or mycophenolate mofetil and other immunosuppressant agents.

Synthesis of mycophenolate mofetil-[14C], RS-61443-14C

Abstract: Synthesis of the potent immunosuppressive agent, mycophenolate mofetil (1) labelled with carbon-14 is described. Methoxyethoxymethyl (MEM) protected mycophenolate norbromide (9) was prepared from unlabelled mycophenolic acid (2) using a modified Hunsdiecker reaction. A three step synthesis furnished the title compound, having a specific activity of 53.8 mCi/mmol, in 49.5% overall yield from K 14 CN

High dose formulations of mycophenolate mofetil and mycophenolic acid

Abstract: Mycophenolate mofetil and mycophenolic acid can be conveniently manufactured into high dose oral formulations by the hot melt filling of a supercooled mycophenolate mofetil or mycophenolic acid liquid into a pharmaceutical dosage form. High dose oral pharmaceutical formulations and manufacturing methods therefor are disclosed.

6-substituted mycophenolic and derivatives with immunosuppressive activity

Abstract: The disclosed 6-substituted derivatives of mycophenolic acid of formula (I) are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil.

4-amino derivatives of mycophenolic acid 5-substituted.

Abstract: BARE DERIVATIVES OF FORMULA mycophenolic acid (IE) THERAPEUTIC AGENTS ARE ADVANTAGEOUS IN THE TREATMENT OF DISEASE INDICATED BY STATES mycophenolic acid and / or mycophenolate mofetil and other immunosuppressive agents. In said formula, Z is a side chain SELECTED FROM THE FORMULAS (ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH).

4-amino 6-substituted mycophenolic acid and derivatives with immunosuppressive activity

Abstract: The disclosed derivatives of mycophenolic acid of formula (I) are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents.

4-amino derivatives of mycophenolic acid with immunosuppressant activity

Abstract: The disclosed derivatives of mycophenolic acid represented by formula (I) are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other imunosuppressant agents.