EDITORIAL - CellCept: a magic bullet for lupus?

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Editorial

June 2005

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Mycophenolate Mofetil: A Magic Bullet for Lupus?

W. JOSEPH McCUNE, MD,

University of Michigan Medical Center;

MONA M. RISKALLA, MD, MS,

Lecturer in Pediatric Rheumatology,

University of Michigan, Ann Arbor, Michigan, USA.

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Mycophenolic acid, the parent drug from which mycophenolate mofetil

(MMF) was synthesized, was isolated from Penicillium species in 18961

at about the same time that quinine was first used for the treatment

of cutaneous lupus. Like quinine, widespread application of

mycophenolic acid (MPA) to lupus awaited synthesis of a more effective

and better tolerated derivative, but the timetable was slower. During

the decades between 1920 and 1960, the quinine derivatives quinacrine,

chloroquine, and hydroxychloroquine were synthesized and gained wide

acceptance for treatment of lupus, particularly cutaneous lupus. Much

later, in the 1960s, MPA was found to have antifungal and anticancer

properties.

Mycophenolic acid was first extensively studied for treatment of

psoriasis in the 1970s, employing heroic doses of 4– 9 grams per day2.

Although MPA was shown to be an effective treatment for psoriasis, its

erratic absorption, short half-life in the blood, and extremely high

incidence of gastrointestinal toxicity precluded widespread use. In

retrospect, unrecognized enzymes in the skin that resynthesize the

active compound, MPA, from the circulating inactive metabolite

mycophenolic acid glucuronide (MPAG) may have contributed to the

effectiveness of MPA in psoriasis.

Introduction of MMF, which is more consistently absorbed than MPA and

is hydrolyzed to MPA in vivo, enabled maintenance of therapeutic serum

levels of MPA utilizing lower and better tolerated daily doses —

usually 2 to 3 grams of MMF. The improved efficacy and markedly

reduced toxicity of MMF led to its widespread use as an

immunosuppressive. Nonetheless, individual differences in the rates of

hepatic metabolism of MPA to MPAG and the renal excretion,

deglucuronidation, and reactivation of MPAG in tissues, including the

intestine and skin, led to substantial variation of MPA concentrations

in individual patients taking MMF. Unfortunately, determining

pharmacokinetics or comparing effective drug levels in individual

patients or clinical trials at this time remains cumbersome and

expensive3.

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Read the entire editorial here:

http://www.jrheum.com/subscribers/05/06/967.html

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