Pharmacokinetics of immunosuppressants

A perspective on ethnic differences

N. L. Dirks, B. Huth, Charles Yates, Bernd Meibohm

Research output: Contribution to journalReview article

84 Citations (Scopus)

Abstract

Despite recent advancements in solid organ transplantation, African-American renal allograft recipients continue to exhibit poorer prognosis in long-term clinical outcome and graft survival compared to Caucasian patients. The role of immunosuppressants in post-transplant outcome is crucial, and associations between exposure-related pharmacokinetic parameters and clinical outcome have been made for several drugs in this class. Thus, ethnic differences in the pharmacokinetics of immunosuppressants are potentially a key factor in the observed differences in post-transplant outcome between African-Americans and Caucasians. Ethnic differences in pharmacokinetics of mycophenolate mofetil and azathioprine based on the current literature are either absent or only of minor relevance. Cyclosporine, tacrolimus, sirolimus and everolimus, however, have all been described to exhibit ethnicity-specific differences in bioavailability and/or dose-adjusted systemic exposure, although currently available reports are controversial for some of these drugs. Oral bioavailability of these drugs in African-Americans was between 20 and 50% lower than in Caucasians or Non-African-Americans, leading to higher dose requirements in African-Americans to maintain similar average concentrations of the respective immunosuppressant. Since all four drugs undergo extensive metabolism and are substrates for CYP3A isoenzymes as well as the drug transporter P-glycoprotein, interethnic variability in activity of these enzymes/transporter may provide a common mechanism for the observed ethnic differences. These ethnic differences are most likely mediated via several non-genetic as well as genetic factors, including known genetic variations that impair transporter/enzyme activity in genes such as CYP3A4, CYP3A5 and ABCB1 (MDR1). Appreciation of differences in immunosuppressant pharmacokinetics and dose requirements between African-Americans and Caucasians in clinical practice is expected to improve post-transplant immunosuppressive pharmacotherapy and may thus contribute to equalize prognostic outcome for all transplant patients.

Original languageEnglish (US)
Pages (from-to)701-718
Number of pages18
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume42
Issue number12
DOIs
StatePublished - Jan 1 2004

Fingerprint

Immunosuppressive Agents
African Americans
Cytochrome P-450 CYP3A
Pharmacokinetics
Transplants
Pharmaceutical Preparations
Biological Availability
Mycophenolic Acid
Azathioprine
P-Glycoprotein
Tacrolimus
Organ Transplantation
Graft Survival
Sirolimus
Enzymes
Cyclosporine
Isoenzymes
Allografts
Kidney
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacokinetics of immunosuppressants : A perspective on ethnic differences. / Dirks, N. L.; Huth, B.; Yates, Charles; Meibohm, Bernd.

In: International Journal of Clinical Pharmacology and Therapeutics, Vol. 42, No. 12, 01.01.2004, p. 701-718.

Research output: Contribution to journalReview article

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