3 research outputs found
Structural Basis of the Change in the Interaction Between Mycophenolic Acid and Subdomain IIA of Human Serum Albumin During Renal Failure
Mycophenolic
acid (MP) is an active metabolite of mycophenolate
mofetil, a widely used immunosuppressive drug. MP normally exhibits
high plasma protein binding (97–99%), but its binding rate
is decreased in patients with renal insufficiency. This decreased
protein binding is thought to be associated with leukopenia, a side
effect of MP. In this study, we characterized the change in protein
binding of MP in renal failure patients. Our findings indicate that
MP binds strongly to subdomain IIA of human serum albumin. X-ray crystallographic
data indicated that the isobenzofuran group of MP forms a stacking
interaction with Trp214, and the carboxyl group of MP is located at
a position that allows the formation of hydrogen bonds with Tyr150,
His242, or Arg257. Due to the specific binding of MP to subdomain
IIA, MP is thought to be displaced by uremic toxin (3-carboxy-4-methyl-5-propyl-2-furan-propionic
acid) and fatty acids (oleate or myristate) that can bind to subdomain
IIA, resulting in the decreased plasma protein binding of MP in renal
failure
Structural Basis of the Change in the Interaction Between Mycophenolic Acid and Subdomain IIA of Human Serum Albumin During Renal Failure
Mycophenolic
acid (MP) is an active metabolite of mycophenolate
mofetil, a widely used immunosuppressive drug. MP normally exhibits
high plasma protein binding (97–99%), but its binding rate
is decreased in patients with renal insufficiency. This decreased
protein binding is thought to be associated with leukopenia, a side
effect of MP. In this study, we characterized the change in protein
binding of MP in renal failure patients. Our findings indicate that
MP binds strongly to subdomain IIA of human serum albumin. X-ray crystallographic
data indicated that the isobenzofuran group of MP forms a stacking
interaction with Trp214, and the carboxyl group of MP is located at
a position that allows the formation of hydrogen bonds with Tyr150,
His242, or Arg257. Due to the specific binding of MP to subdomain
IIA, MP is thought to be displaced by uremic toxin (3-carboxy-4-methyl-5-propyl-2-furan-propionic
acid) and fatty acids (oleate or myristate) that can bind to subdomain
IIA, resulting in the decreased plasma protein binding of MP in renal
failure
Angiogenesis inhibitor-specific hypertension increases the risk of developing aortic dissection
Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p<0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients