Role of Plasma Lipoproteins in Modifying the Biological Activity of Hydrophobic Drugs

Wasan, Kishor M.; Cassidy, Shawn M.

doi:10.1021/js970407a

Cited by 130 publications

(107 citation statements)

References 105 publications

(157 reference statements)

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…They may also act as carriers of several hydrophobic drugs within the circulation and are the major protein class involved in the binding of CyA in plasma. 18 In normolipidemic (NL) human plasma, 31% of CyA is associated with combined low-density lipoprotein (LDL) and very low density lipoprotein (VLDL) E673 classes, 44% with high-density lipoprotein (HDL), and 20% with other protein classes such as albumin. 19 In hyperlipoproteinemic (HL) human plasma there is a shift of drug into the LDL/VLDL fractions from the HDL fraction.…”

Section: Introductionmentioning

confidence: 99%

Insights into the effects of hyperlipoproteinemia on cyclosporine A biodistribution and relationship to renal function

Aliabadi

Spencer

Mahdipoor

et al. 2006

AAPS J

View full text Add to dashboard Cite

The purpose of this study was to assess the effect of hyperlipoproteinemia on the biodistribution of cyclosporine A (CyA), an extensively lipoprotein bound immunosuppressant, in a rat model and to determine the potential toxicological signifi cance of this effect. Normolipidemic and hyperlipoproteinemic rats were given a single 5 mg/kg dose of CyA as intravenous bolus and at selected times postdose, tissues, blood, and plasma were harvested and assayed for CyA content. Hyperlipoproteinemia was induced by intraperitoneal injection of 1 g/kg poloxamer 407. Compared with normolipidemic animals, hyperlipoproteinemic rats had higher plasma, blood, kidney, and liver CyA concentrations. In contrast, in heart and spleen the concentrations were decreased in hyperlipoproteinemia. The nephrotoxic effect of CyA was also evaluated in normolipidemic and hyperlipoproteinemic rats after 7 days of dosing with 20 mg/kg/day. In both groups of animals, repeated doses of CyA were associated with equivalent decreases in creatinine and urea clearances compared with matching control and predose baseline measures. The concentrations of drug in kidney were equivalent at the conclusion of the study. However, despite these similarities there was microscopic evidence of more severe changes in the kidneys in the hyperlipoproteinemic rats, which also experienced a signifi cant decrease in body weight compared with the normolipedemic animals. In conclusion, the distribution of CyA to kidneys was enhanced in poloxamer 407 -induced hyperlipoproteinemic rats after single doses, and with repeated doses there was an apparent greater adverse effect on these animals compared with normolipidemic animals.

show abstract

Section: Introductionmentioning

confidence: 99%

Insights into the effects of hyperlipoproteinemia on cyclosporine A biodistribution and relationship to renal function

Aliabadi

Spencer

Mahdipoor

et al. 2006

AAPS J

View full text Add to dashboard Cite

show abstract

“…The values of t max in the different fractions do not differ significantly and the increase in the DAI concentration occurs simultaneously. This phenomenon cannot be explained by the fact that DAI is absorbed by the chylomicron pathway because it takes about 4 h before chylomicron remnants are taken up by the liver and DAI is transferred from chylomicrons to lipoproteins of 10·4 2·4 5·9 2·0 16·1 4·7 244·4 63·9 2·9 VLDL 59·0 55·3 8·4 1·5 14·7 6·6 974·4 757·2 11·6 LDL 64·6 16·8 8·4 1·5 14·2 5·9 1806·0 837·9 21·5 HDL 32·5 13·8 9·2 1·0 15·2 4·7 892·1 392·1 13·9 Non-lipoprotein fraction 208·6 63·6 8·0 1·3 15·7 9·5 4195·9 610·5 50·1 Total 10 higher density after lipolysis and remodelling (7) . The observed distribution seems to be due to unspecific isoflavone binding to proteins.…”

Section: Discussionmentioning

confidence: 99%

Role of plasma lipoproteins in the transport of the soyabean isoflavones daidzein and daidzein-7-O-β-d-glucoside

et al. 2009

View full text Add to dashboard Cite

Isoflavone intake is associated with various properties beneficial to human health which are related to their antioxidant activity, for example, to their ability to increase LDL oxidation resistance. However, the distribution of isoflavones among plasma lipoproteins has not yet been elucidated in vivo. Therefore, the objective of the present study was to investigate the association between daidzein (DAI) and lipoproteins in human plasma upon administration of the aglycone and glucoside form. Five men aged 22-30 years participated in a randomised, double-blind study in cross-over design. After ingestion of DAI and daidzein-7-O-b-D-glucoside (DG) (1 mg DAI aglycone equivalents/kg body weight) blood samples were drawn before isoflavone administration as well as 1, 2, 3, 4·5, 6, 8, 10, 12, 24 and 48 h post-dose. Concentrations of DAI in the different lipoprotein fractions (chylomicrons, VLDL, LDL, HDL) and in the non-lipoprotein fraction were analysed using isotope dilution capillary GC/MS. The lipoprotein fraction profiles were similar for all subjects and resembled those obtained for plasma in our previously published study. The lipoprotein distribution based on the area under the concentration -time profiles from 0 h to infinity in the different fractions were irrespective of the administered form: non-lipoprotein fraction (53 %) . LDL (20 %) . HDL (14 %) . VLDL (9·5 %) . chylomicrons (2·5 %). Of DAI present in plasma, 47 % was associated to lipoproteins. Concentrations in the different lipoprotein fractions as well as in the non-lipoprotein fraction were always higher after the ingestion of DG than of DAI. Taken together, these results demonstrate an association between isoflavones and plasma lipoproteins in vivo. Dietary isoflavones, a subclass of flavonoids, have been the focus of much of the recent interest in the nutritional benefits of soya foods (1) . The exact role that isoflavones play in the health-related effects of soya foods and their potential for adverse effects have been controversial and difficult to discern (2,3) . This may be in part due to the lack of basic knowledge regarding absorption, distribution, metabolism and excretion.In a recently published study, we investigated the difference in the bioavailability of the isoflavone daidzein (DAI) in the aglycone and glucoside form when administered as pure compounds (4) . In most subjects the plasma appearance and disappearance curves revealed a biphasic pattern with an early peak before the peak plasma concentration which has also been reported by other authors (5,6) . Possible reasons for this behaviour discussed so far are enterohepatic recycling and some small initial absorption in the upper gastrointestinal tract along with predominant absorption in the large intestine.A third explanation might be the absorption of isoflavones via a chylomicron-mediated mechanism and distribution of isoflavones bound to lipoproteins throughout the body. Several observations provide evidence for this hypothesis: It is known that water-insoluble compounds, for...

show abstract

“…Lipoproteins are a heterogeneous population of macromolecular aggregates of lipids and proteins that are responsible for the transport of lipids through the vascular and extravascular fluids from their site of synthesis or absorption to peripheral tissues 1,2 . Lipids, which include Triglycerides (TG) and cholesteryl esters (CE), are delivered from the liver and intestine to other tissues for storage or catabolism in the production of energy.…”

Section: Introductionmentioning

confidence: 99%

“…Lipids, which include Triglycerides (TG) and cholesteryl esters (CE), are delivered from the liver and intestine to other tissues for storage or catabolism in the production of energy. Lipoproteins are involved in other biological processes as well, including coagulation and tissue repair, and serve as carriers of a number of hydrophobic compounds within the systemic circulation 1,2 .…”

Section: Introductionmentioning

confidence: 99%

Role of plasma lipoproteins in modifying the toxic effects of water-insoluble drugs: Studies with cyclosporine A

Ramaswamy

Kwong

Boulanger

2002

AAPS J

Self Cite

View full text Add to dashboard Cite

Lipoproteins are a heterogeneous population of macromolecular aggregates of lipids and proteins that are responsible for the transport of lipids through the vascular and extravascular fluids from their site of synthesis or absorption to peripheral tissues. Lipoproteins are involved in other biological processes as well, including coagulation and tissue repair, and serve as carriers of a number of hydrophobic compounds within the systemic circulation. It has been well documented that disease states (eg, AIDS, diabetes, cancer) significantly influence circulating lipoprotein content and composition. Therefore, it appears possible that changes in the lipoprotein profile would affect not only the ability of a compound to associate with lipoproteins but also the distribution of the compound within the lipoprotein subclasses. Such an effect could alter the pharmacokinetics and pharmacological action of the drug. This paper reviews the factors that i nfluence the interaction of one model hydrophobic compound, cyclosporine A, with lipoproteins and the implications of altered plasma lipoprotein concentrations on the pharmacological behavior of this compound.

show abstract

Role of Plasma Lipoproteins in Modifying the Biological Activity of Hydrophobic Drugs

Cited by 130 publications

References 105 publications

Insights into the effects of hyperlipoproteinemia on cyclosporine A biodistribution and relationship to renal function

Insights into the effects of hyperlipoproteinemia on cyclosporine A biodistribution and relationship to renal function

Role of plasma lipoproteins in the transport of the soyabean isoflavones daidzein and daidzein-7-O-β-d-glucoside

Role of plasma lipoproteins in modifying the toxic effects of water-insoluble drugs: Studies with cyclosporine A

Contact Info

Product

Resources

About