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Pharmacokinetics of Oral Mycophenolate Mofetil in Volunteer Subjects with Varying Degrees of Hepatic Oxidative Impairment
Author(s) -
Parker Gerry,
Bullingham Roy,
Kamm Barbara,
Hale Michael
Publication year - 1996
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1996.tb04209.x
Subject(s) - glucuronidation , pharmacokinetics , mycophenolic acid , medicine , cirrhosis , gastroenterology , mycophenolate , volunteer , urine , liver disease , creatinine , pharmacology , transplantation , chemistry , biochemistry , agronomy , biology , enzyme , microsome
Eighteen patients with compensated alcoholic cirrhosis participated in a single‐dose pharmacokinetic study of oral mycophenolate mofetil (MMF). Participants were divided into groups of 6 patients each with mild, moderate, or severe hepatic oxidative impairment as defined by the aminopyrine breath test (APBT). Clinically, hepatic disease was of mild or moderate severity. Six healthy volunteers were included as control subjects. Plasma and urine samples were collected over 96 hours and assayed for the active metabolite mycophenolic aced (MPA) and the glucuronide conjugate, MPAG. Plasma protein binding of MPA also was determined in 6 unrelated patients with cirrhosis. Cirrhosis did not grossly affect plasma pharmacokinetics or plasma binding of MPA. Maximum plasma concentrations (C max ) and area under the curve (AUC) of MPA and MPAG consistently decreased, increased, and then decreased as oxidative impairment declined from normal to severe. Patients with cirrhosis had comparable or greater recovery of administered drug substance in urine than controls, showing that cirrhosis did not affect the extent of MMF absorption. Urine clearance of MPAG was two times higher in the group with severe impairment than in the other groups. Creatinine clearance was similar in all groups. These results suggest progressive impairment of hepatic glucuronidation of MPA and induction of renal glucuronidation in patients with severe hepatic oxidative impairment.