Species- and Gender-Related Differences in Cyclosporine/Prednisolone/Sirolimus Interactions in Whole Blood Lymphocyte Proliferation Assays1
Abstract
Cyclosporin A (CyA), prednisolone (Pred) and sirolimus (Sir) inhibit lymphocyte proliferation at the cytokine transcription (CyA and Pred) or signal transduction (Sir) levels. Their double and triple interactions were studied on lectin-induced proliferation of whole blood lymphocytes (WBLP) from male and female humans, rabbits and rats. Isobols along with the Universal Response Surface Approach were used to describe and quantify the nature and intensity of drug interactions by determining α values. CyA was always less potent than Pred and Sir while these two compounds were relatively equipotent. Species-related differences were observed with single drugs. Rabbit WBLP were resistant to Pred action (Imax = 67%) and rats were more sensitive to Pred (IC50 = 9.1 nM in females) and Sir (2.8 nM) actions than humans (32 and 55 nM). Gender differences were observed but were not consistent across species. All double-drug combinations were synergistic, and combinations containing Pred were 10 to 100 times more synergistic in rabbits (αPred/Sir = 213 and αCyA/Pred = 147 in males) than in rats (12 and 2.1) or humans (3.7 and 5.7) in relation to the lower efficacy of Pred. Double-combination α values were able to describe CyA/Pred/Sir triple combination effects. These studies indicate that CyA, Pred and Sir act and synergistically interact in vitro in species- and gender-dependent fashions. Adrenalectomized rats better resemble humans in these responses. WBLP are useful in various species in determining immunosuppressive drug action and interactions.
Footnotes
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Send reprint requests to: William J. Jusko, Ph.D., Department of Pharmaceutics, State University of New York at Buffalo, 565 Hochstetter Hall, Buffalo, NY 14260.
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↵1 This work was supported by grant GM 24211 from the National Institutes of Health, Bethesda, MD and Fellowship support for G.M.F. from Wyeth-Ayerst Research, Radnor, PA.
- Abbreviations:
- α
- double drug interaction parameter using URSA
- Back
- % of Smax not affected by the drug
- CyA
- cyclosporin A
- γ
- slope of the concentration effect relationship
- GLS
- general least squares procedure
- IC50
- drug concentration producing response equal to 50% ofSmax − Back
- HEPES
- N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
- ICAM-1
- intracellular adhesion molecule-1
- IL
- interleukin
- Imax
- maximum inhibition
- LFA-1
- lymphocyte function-associated antigen-1
- PHA-L
- phytohemagglutinin-L
- Pred
- prednisolone
- Sir
- Sirolimus (Rapamycin)
- Smax
- maximum stimulation (100%)
- URSA
- universal response surface approach
- WBLP
- whole blood lymphocyte proliferation
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- Received September 8, 1997.
- Accepted March 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
