This study will examine how people differ in the way their bodies process and eliminate
mycophenolate mofetil (MMF), a drug that is used to treat problems affecting the eye and
immune system and to prevent organ rejection in transplant patients. MMF is metabolized by a
group of enzymes called UGTs, each of which is made by a different gene. This study will
investigate whether people with different UGT genes differ in how well their bodies use and
remove MMF. The results may help scientists learn the best way to give MMF to patients.
Normal healthy volunteers between 18 and 55 years of age may be eligible for this study.
Candidates are screened with a medical history, physical examination, and blood and urine
tests, including a blood test for analysis of genes that control and regulate UGTs. Pregnant
women and nursing mothers are excluded from the study. Women who are able to have a child
and men who can father a child must either abstain from sex or use two reliable forms of
birth control during the study and for 3 months after its completion.
Participants come to the NIH Clinical Center at 6:30 a.m. on the first day of the study and
stay in the outpatient clinic for 12 hours. The next 4 mornings, they return to the Clinical
Center for a single blood collection. The procedures for the 5 days are as follows:
Upon arrival at the Clinical Center a catheter is inserted into the subject's arm vein. At
7:00 AM, the subject takes one dose of MMF by mouth with a glass of water. Small blood
samples are collected through the catheter before the MMF dose and again at 0.5, 1, 1.5, 2,
3, 4, 6, 8, 10, and 12 hours after taking the drug. Heart rate and blood pressure are
measured before the blood collection and then every 4 hours. After the last blood sample is
collected, the volunteer can return home.
Volunteers come to the Clinical Center at 7:00 AM on study days 2, 3, 4, and 5 for a single
blood draw, collected using a needle.
Volunteers are contacted by telephone 1, 2, and 3 months after completing the study to see
how they are doing and to check on their pregnancy status and use of appropriate birth
The immunosuppressant mycophenolate mofetil (MMF) is metabolized by several uridine
diphosphate glucuronosyltransferases (UGTs), among which UGT1A9 is the most important
enzyme. Two commonly occurring single nucleotide polymorphisms (SNPs) in the promoter
region of the UGT1A9 gene have been shown to enhance UGT1A9 protein level and activity in
vitro. This study is to investigate the potential in vivo effects of these two SNPs on the
metabolism and hence the pharmacokinetics of MMF metabolites. One hundred and thirty
healthy volunteers will be screened for the presence of UGT1A9 C-2152T and T-275A
polymorphisms. Seventeen subjects who carry the variant alleles, along with 17 others who
do not have the polymorphisms, will be selected to participate in the pharmacokinetic study.
Pharmacokinetics of the metabolites mycophenolic acid (active) and mycophenolate
7-O-phenolic glucuronide (inactive) will be determined, and parameter values will be
compared between the two groups. It is hypothesized that the metabolism of MMF is enhanced
in subjects with the two SNPs, resulting in an increase in clearance and a decrease in the
exposure of mycophenolic acid.
- Normal healthy volunteers who are in good health as determined by medical history,
physical examination, and baseline laboratory tests
- Age 18 - 55
- Both males and females
- Willingness to practice effective contraception during the study and for three months
after the administration of MMF for women who are sexually active and have child
bearing potential, and for sexually active males who have the potential to father a
child. Barrier or non-hormonal methods will be allowed during the study, whereas the
use of oral, injectable, or implantable hormones will be prohibited since drug
interaction is known to occur between oral contraceptives and mycophenolate mofetil.
- Subjects who are able to understand and sign the informed consent form.
- Children and adolescents less than 18 years of age
- Individuals who smoke or have excessive alcohol (greater than 1 beer or an equivalent
alcoholic beverage per day)
- Pregnant women and nursing mothers
- Subjects with certain underlying diseases which include diabetes, cardiovascular
diseases, liver diseases, cancer, and human immunodeficiency virus infection
- Individuals with compromised immune systems
- Subjects who have an active infection
- Individuals with history of biliary tract disease, and biliary or gastrointestinal
- Subjects with persistent diarrhea or other gastrointestinal problems that could
impede drug absorption
- Subjects with abnormal liver and kidney functions as determined by medication history
and laboratory evaluation (AST and ALT less than or equal to 2 x upper normal limit,
total bilirubin less than or equal to 1 mg/dL, serum creatinine less than or equal to
1.2 mg/dL, hemoglobin greater than or equal to 11 g/dL, WBC greater than or equal to
3.5 x 10(9)/L)
- Volunteers on chronic prescribed and over-the-counter medications, and dietary and
herbal supplements within 4 weeks of study participation
- Subjects who are taking any medications that could potentially interact with MMF
pharmacokinetically and pharmacodynamically such as eccinacea, iron preparations,
antacids, bile-resin cholesterol lowering agents, and steroids.
- Volunteers with documented allergy to MMF
- Prior enrollment into a similar study within the past two months and enrollment in
another study at the same time
- Subjects who are felt to be unwilling or unable to practice effective contraception
methods or comply with protocol specifications