Altered chain-length and glycosylation modify the pharmacokinetics of human serum albumin.
Human serum albumin with modified plasma half-life will be useful for clinical purposes. Therefore, the pharmacokinetics of three of each of the following types of genetic variants, and of their corresponding normal albumin, were examined in mice: N-terminally elongated, C-terminally truncated and glycosylated albumins. Isoforms differing from the normal protein by three or more amino acids, especially two of the truncated forms, had shorter half-lives. The effect of glycosylation depended on the position of attachment: in domain II it increased half-life, whereas in domain I and III it had no significant effect. Liver, kidney and spleen uptake clearances were also modified. The pronounced changes in half-life of the two truncated variants and the glycosylated isoform could be explained, at least partly, by large changes in organ uptakes; in the remaining six cases, different effects were registered. Such information should be useful when designing therapeutical albumin products for, e.g., drug delivery systems. In addition to various types of cell endocytosis, leading to intracellular destruction or recycling of the proteins, the metabolism of the alloalbumins could be affected by plasma enzymes. No correlation was found between mutation-induced changes in the pharmacokinetic parameters and changes in alpha-helical content or changes in heat stability as represented by DeltaH(v).
Iwao
Yasunori
Y
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Hiraike
Mikako
M
Kragh-Hansen
Ulrich
U
Kawai
Keiichi
K
Suenaga
Ayaka
A
Maruyama
Toru
T
Otagiri
Masaki
M
D000595:Amino Acid Sequence; D000818:Animals; D006031:Glycosylation; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D055550:Protein Stability; D012709:Serum Albumin / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*; D000075462:Serum Albumin, Human; D013154:Spleen / Q000378:metabolism
D012709:Serum Albumin; C030763:alloalbumins; D000075462:Serum Albumin, Human