Albumin binding and time action of acylated insulins in various species.
ABSTRACT Insulins acylated with fatty acids at the epsilon-amino group of LysB29 constitute a new class of insulin analogs, which are prolonged-acting due to albumin binding. In the present study it is shown that the affinity of fatty acid acylated insulins for albumin varies considerably (> 50-fold) among species. The relative affinities of acylated insulin for albumin in human, pig, and rabbit serum are about 1:1:5:35. The several fold higher binding affinity in rabbit serum than in pig serum is reflected in a relatively more protracted effect after sc injection in rabbits than in pigs. Due to the similar binding affinities in pig serum and human serum, the pig model should provide a useful estimate of the degree of protraction of acylated insulin in humans. The results emphasize that species differences in ligand binding can be of major importance in the preclinical evaluation of highly albumin bound drugs.
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ABSTRACT: Depending upon the drug and drug delivery platform, species-specific physiological differences can lead to errors in the interspecies extrapolation of drug performance. This manuscript provides an overview of the species-specific physiological variables that can influence the performance of parenteral dosage forms such as in situ forming delivery systems, nanoparticles, microspheres, liposomes, targeted delivery systems, lipophilic solutions, and aqueous suspensions. Also discussed are those factors that can influence the partitioning of therapeutic compounds into tumors, the central nervous system and the lymphatics. Understanding interspecies differences in the movement and absorption of molecules is important to the interpretation of data generated through the use of animal models when studying parenteral drug delivery.The AAPS Journal 12/2011; 13(4):632-49. · 4.39 Impact Factor
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ABSTRACT: The effects of insulins detemir (Det) and glargine (Glar) on endogenous glucose production (EGP) and net hepatic glucose output (NHGO) were compared. Arteriovenous difference and tracer ([3-(3) H]glucose) techniques were employed during a two-step hyperinsulinemic euglycaemic clamp in conscious dogs (6 groups, n = 5-6/group). After equilibration and basal sampling (0-120 min), somatostatin was infused and basal glucagon was replaced intraportally. Det or Glar was infused via portal vein (Po), peripheral vein (IV), or bilateral carotid and vertebral arteries (H) at 0.1 and 0.3 mU/kg/min (low Insulin; Glar vs. Det, respectively, 120-420 min) and 4× the low insulin rate (high insulin; 420-540 min). NHGO and EGP were suppressed and glucose R(d) and infusion rate were stimulated similarly by Det and Glar at both Low and high insulin with each infusion route. Non-esterified fatty acid (NEFA) concentrations during low insulin were 202 ± 37 versus 323 ± 75 µM in DetPo and GlarPo (p < 0.05) and 125 ± 39 versus 263 ± 48 µM in DetIV and GlarIV, respectively (p < 0.05). In DetH versus GlarH, pAkt/Akt (1.7 ± 0.2 vs. 1.0 ± 0.2) and pSTAT3/STAT3 (1.4 ± 0.2 vs. 1.0 ± 0.1) were significantly increased in the liver but not in the hypothalamus. Det and Glar have similar net effects on acute regulation of hepatic glucose metabolism in vivo regardless of delivery route. Portal and IV detemir delivery reduces circulating NEFA to a greater extent than glargine, and head detemir infusion enhances molecular signalling in the liver. These findings indicate a need for further examination of Det's central and hepatic effects.Diabetes Obesity and Metabolism 05/2011; 13(9):832-40. · 5.18 Impact Factor
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ABSTRACT: Aging is associated with alterations in insulin secretion and action. However, aging per se does not alter the pharmacokinetics of commercially available insulin and its analogues. Insulin therapy in older adults is complicated by psychosocial and physiological changes of aging. Several new insulin and insulin analogue preparations are now available for clinical use. Used as prandial (e.g. insulin lispro, insulin aspart or insulin glulisine) and basal insulin (e.g. insulin glargine, insulin detemir), these analogues simulate physiological insulin profiles more closely than the older conventional insulins. The availability of multiple insulin products provides new opportunities to achieve control of diabetes mellitus. The choice of initial insulin therapy can be made based on blood glucose profiles. Overall, these profiles can be divided into three general patterns that include: (i) round-the-clock hyperglycaemia; (ii) fasting hyperglycaemia with daytime euglycaemia; and (iii) daytime hyperglycaemia with normal fasting blood glucose levels. The prescription of insulin is a dynamic process, and the insulin regimen should be adjusted based on individual response. The goal of diabetes care in older adults is to enhance quality of life without subjecting individuals to complicated treatment regimens that may interfere with their independence in carrying out daily activities.Drugs & Aging 06/2011; 28(6):429-38. · 2.65 Impact Factor