Methylprednisolone dosage effects on peripheral lymphocyte subpopulations and eicosanoid synthesis.
Glucocorticoids have a major role in the treatment of glomerular diseases. Despite recent advances in understanding of their mechanism of action, very few studies have addressed the relative advantage of the wide range of different dose regimens employed in clinical practice. We studied the effects of methylprednisolone given intravenously for three consecutive days at the doses of 1 mg/kg (group 1, N = 7; group 2, N = 5), 5 mg/kg (group 3, N = 5) or 15 mg/kg (group 4, N = 6) on total blood peripheral leukocytes and on lymphocyte subsets in patients with glomerular diseases, and investigated whether such effects were a function of the drug concentration in the blood. Since glucocorticoids have an inhibitory effect on the formation of eicosanoids in different cells, we also investigated in the same patients the effect of 1 and 15 mg/kg methylprednisolone on systemic and renal eicosanoid synthesis. Results of pharmacokinetic study showed that the three different doses of methylprednisolone we used resulted in major differences in patient's exposure to the drug, and within the same dose there was a great individual variability. By contrast the three different doses of methylprednisolone induced a comparable drop in the absolute number of lymphocytes six hours after the first injection of methylprednisolone, while 24 hours later blood lymphocyte counts returned to the pre-injection values in all patients. Analysis of lymphocyte subsets showed a selective decrease in the number of circulating CD4+ and CD8+ cells six hours after methylprednisolone which was comparable in the four groups of patients studied. As for the effect of methylprednisolone on systemic and renal eicosanoid synthesis in patients with glomerular diseases, 1 and 15 mg/kg were equally unable to reduce thromboxane A2 (TxA2) and prostaglandin E2 (PGE2) release by circulating polimorphonuclear cells (PMNs). By contrast, methylprednisolone partially inhibited eicosanoid synthesis by PMNs in vitro. Consistent with the data on PMNs, urinary excretion of TxA2 and prostacyclin (PGI2) metabolites were unaltered by the different doses of methylprednisolone. By contrast urinary PGE2 was markedly and significantly reduced in patients given 15 but not 1 mg/kg. We conclude that 1 mg/kg methylprednisolone given to patients with glomerular diseases has the same effect on peripheral total blood leukocyte count and lymphocyte subsets than 5 and 15 mg/kg. The same is true for eicosanoid synthesis by PMNs. Renal synthesis of PGE2 is inhibited by 15 mg/kg but not by 1 mg/kg.(ABSTRACT TRUNCATED AT 400 WORDS)
Rota
S
S
Division of Nephrology and Dialysis, Ospedali Riuniti di Bergamo, Bergamo, Italy.
Rambaldi
A
A
Gaspari
F
F
Noris
M
M
Daina
E
E
Benigni
A
A
Perna
A
A
Donadelli
R
R
Remuzzi
G
G
Garattini
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D016131:Lymphocyte Subsets / Q000187:drug effects*; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000097:blood; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism; D013929:Thromboxane B2 / Q000096:biosynthesis
D015777:Eicosanoids; D013929:Thromboxane B2; D015232:Dinoprostone; D008775:Methylprednisolone