Abstract
Pharmacokinetics and pharmacodynamics of insulin analogues were compared with human insulin in streptozotocin-induced chronic diabetic Yucatan minipigs. After overnight fasting, insulin or one of the insulin analogues (0.6 nmol/kg) in acid solutions (pH ∼3.0) was administered to the minipigs s.c. The plasma insulin concentrations were then measured by radioimmunoassay at predetermined time intervals although blood glucose levels were monitored continuously. The mean (±S.E.) values of ΔCmax (difference between peak and basal plasma insulin levels) were 598 (±21), 528 (±44), 176 (±21), 325 (±60) and 228 (±33) pM, respectively, for analogue AspB9GluB27, AspB9, GluB27, AspB28 and insulin. The differences in ΔCmax values were statistically significant between AspB9GluB27 and insulin (P < .02), and between AspB9 and insulin (P < .01), but not between GluB27 or AspB28 and insulin. Moreover, the mean (±S.E.) values of ΔAUC0→6 (integrated area between plasma insulin concentration curve and basal level) were 1877 (±169), 1897 (±70), 485 (±36), 500 (±32) and 677 (±105) pM × hr, respectively, for AspB9GluB27, AspB9, GluB27, AspB28 and insulin. The differences in ΔAUC0→6 values were statistically significant between AspB9GluB27 and insulin (P < .05) and between AspB9 and insulin (P < .02), but not between GluB27 or AspB28 and insulin. However, there was no significant difference in the values of Δnadir (difference between nadir and basal levels) and ABGC0→12 (integrated area between blood glucose response curve and basal level) between insulin and various analogues. In conclusion, although the insulin analogues are different from human insulin in pharmacokinetics, they exhibit similar biological activity to human insulin in the streptozotocin-induced chronic diabetic minipigs.
Footnotes
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Send reprint requests to: Dr. Yie W. Chien, Controlled Drug-Delivery Research Center, Rutgers University, College of Pharmacy, 41 Gordon Road, Suite D, Piscataway, NJ 08854-8067.
- Abbreviations:
- CI
- confidence interval
- MRT
- mean residence time
- ABGC
- the integrated area between glucose response curve and basal blood glucose
- PE
- polyethylene
- STZ
- streptozotocin
- TDMAC-heparin
- tridodecylmethylammonium chloride-heparin
- Received July 11, 1997.
- Accepted April 13, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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