Abstract

Kid goats (newborn) have been used in transplantation protocols to study the techniques and problems of infant human cardiac transplantation. Immunosuppression has been by cyclosporine in both species. However, the pharmacokinetics of cyclosporine (CSA) in both the kid goat and human infant were unknown. Therefore, the pharmacokinetics of CSA were investigated. A single dose study and a long term chronic administration study were undertaken in the goat. Six Nubian goats, ages 60-90 days, were given a single IV dose of CSA, 0.25 mg/kg, over a 10 minute period and 72 hr later an oral cyclosporine dose of 20 mg/kg. The mean area under the concentration-time curve (AUC) IV was 1920 ± 208 ng-hr/mL (SEM) versus oral 6210 ± 685 ng-hr/mL . The IV mean residence time (MRT) was 2.1 ± 0.1 hr with a calculated half-life of 1.6 ± 0.1 hr as compared to the oral MRT 15.1 hr with a calculated half-life 7.8 hr. Clearance IV was 139 ± 17 mL/hr/kg. Apparent volume of distribution (Vd) for IV was 0.32 ± 0.04 L/kg as compared to oral 1.3 L/kg with a bioavailability (F) of 3.7% Four Nubian goats, ages less than one week, were administered the same doses of CSA as the single dose study for a period of 12 weeks. The mean AUCs were at least 26-fold higher during the first six weeks as compared to the last six weeks. The MRT and Vd were about the same in both studies with F up to 100%, decreasing to 15% after weaning due to the closure of the ruminal groove in the long term study. Blood chemistries that were affected by CSA were magnesium, glucose and cholesterol. For the human infant, the two-part study consisted of immediate post cardiac transplant, mean 4.9 ± 0.3 days (SEM) and long term, mean age 16.8 ± 2.3 months with time post-transplant of 14.3 ± 2.0 months. Oral doses of CSA increased slightly between immediate post-transplant (6.1 ± 0.3 mg/kg) and long term (6.6 ± 0.7 mg/kg). MRT (5.1 ± 0.1 hr versus 4.0 ± 0.1 hr) and calculated half-lives (7.8 ± 0.9 hr versus 2.9 ± 0.2 hr) decreased but AUC/hr increased (255 ± 18 ng/mL versus 337 ± 22 ng/mL), respectively. Time to peak concentrations did not significantly change in either study. Bioavailability during the immediate post-transplant period was 26% ± 0.3. Five of the long term patients who had been switched to 3 times/day dosing had AUCs of 3538 ± 126 ng-hr/mL as compared to 2 times/day dosing with AUCs of 3491 ± 197 ng-hr/mL. Mean daily cyclosporine doses for the long term patients were 15.4 ± 1.8 mg/kg/day. Blood chemistries that CSA affected were magnesium, cholesterol, glucose, total protein and albumin. In comparing the immediate post cardiac transplant recipient with the the long term post transplant cardiac recipient, CSA doses increased slightly, bioavailabilities increased and MRT was decreased. Changing to a 3 times/day dosing interval can decrease the peak concentrations and still maintain an adequate level of CSA.

LLU Discipline

Pharmacology

Department

Pharmacology

School

Graduate School

First Advisor

Ian M. Fraser

Second Advisor

Allen Strother

Third Advisor

Marvin A. Peters

Fourth Advisor

Ralph E. Cutler

Fifth Advisor

William C. Eby

Sixth Advisor

Steven C. Forland

Seventh Advisor

Leonard L. Bailey

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level

Ph.D.

Year Degree Awarded

1990

Date (Title Page)

12-1990

Language

English

Library of Congress/MESH Subject Headings

Cyclosporins -- pharmacokinetics; Cyclosporins -- in infancy & childhood; Cyclosporins -- chemistry; Goats

Type

Dissertation

Page Count

v; 187

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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