title: In-vivo distribution and erythrocyte binding characteristics of cyclosporin in renal transplant patients.
abstract: The pharmacokinetic parameters of cyclosporin, a potent immunosuppressive agent, show large intra- and inter-individual variability, possibly because of the different analytical methods used. A recently developed cyclosporin-specific radioimmunoassay has been used to study the in-vivo distribution and binding characteristics of cyclosporin in whole blood, plasma and erythrocytes of fifteen renal transplant patients. The profiles of cyclosporin concentration-time curves after an oral dose of cyclosporin had either one peak (ten patients, group A) or two (five patients, group B). Essentially no difference was observed between the two groups in the relationship between equilibrium cyclosporin concentrations in erythrocyte and plasma as a function of whole-blood concentration. The equilibrium in-vivo cyclosporin concentrations in erythrocyte and plasma were, however, markedly lower than those previously observed under in-vitro conditions. The ratio of cyclosporin concentration in erythrocytes (CE) to that in plasma (CP) changed with time, in inverse proportion to the change in cyclosporin concentration in blood, over the range 0.63-2.80 in individual patients with an average of 1.36 +/- 0.07 (mean +/- s.e.m.) for group A and 1.42 +/- 0.23 for group B. The apparent cyclosporin binding affinity (Kd) to erythrocytes under in-vivo conditions averaged 452.2 +/- 47.6 nM (543.5 +/- 57.2 ng mL-1) for group A and 419.4 +/- 41.2 nM (504.1 +/- 49.5 ng mL-1) for group B, whereas apparent cyclosporin binding capacity (Bmax) of the blood cell averaged 0.83 +/- 0.07 nmol mL-1 for group A and 0.78 +/- 0.07 nmol mL-1 for group B. Significantly reduced average Kd (262.7 +/- 40.2 nM or 315.8 +/- 48.9 ng mL-1, P < 0.01) and Bmax (0.56 +/- 0.08 nmol mL-1, P < 0.05) values were observed during the period after Tmax (4-12 h after the drug ingestion) in group A patients. Apparent Kd and Bmax, determined by a nonlinear regression technique, were 131.6 +/- 29.4 and 1088.0 +/- 114.7 nM (158.2 +/- 35.4 and 1307.8 +/- 137.9 ng mL-1) and 0.178 +/- 0.024 and 0.814 +/- 0.078 nmol mL-1, respectively, during the 4-12 h period in group A patients. These findings reveal distinct differences in in-vivo distribution of cyclosporin and the binding characteristics of the compound to erythrocytes from those previously observed under in-vitro conditions. The significantly lower Kd of cyclosporin binding to erythrocytes during the elimination phase suggests a potential effect of cyclosporin-containing erythrocytes or of cyclosporin contained in erythrocytes during cyclosporin treatment.
authors.affiliation: Laboratory of Pharmaceutical Sciences, Osaka University School of Medicine, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kurokawa
authors.forename: M
authors.initials: M
authors.lastname: Kadobayashi
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Arakawa
authors.forename: M
authors.initials: M
authors.lastname: Sawada
authors.forename: S
authors.initials: S
authors.lastname: Takahara
authors.forename: A
authors.initials: A
authors.lastname: Okuyama
authors.forename: C
authors.initials: C
authors.lastname: Yanaihara
mesh_terms: D000328:Adult; D002648:Child; D016572:Cyclosporine / Q000097:blood* / Q000493:pharmacokinetics; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011863:Radioimmunoassay
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine