Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of NBEs in humans can be successfully obtained early...

Collagen turnover in normal and degenerate human intervertebral discs as determined by the racemization of aspartic acid

Knowledge of rates of protein turnover is important for a quantitative understanding of tissue synthesis and catabolism. In this work, we have used the racemization of aspartic acid as a marker for the turnover of collagen obtained from healthy and pathological human intervertebral disc matrices. We measured the ratio of the D- and L-isomers in...

Plasma plasminogen activator inhibitor-1 level is not regulated by the hepatic low-density lipoprotein receptor-related protein [2]

Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue

Objective - The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia. Methods and Results - Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35...

Tissue distribution of quercetin in rats and pigs

Quercetin is a dietary polyphenolic compound with potentially beneficial effects on health. Claims that quercetin has biological effects are based mainly on in vitro studies with quercetin aglycone. However, quercetin is rapidly metabolized, and we have little knowledge of its availability to tissues. To assess the long-term tissue distribution...

CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance

CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient (cd36-/-) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36-/- mice. cd36-/- mice showed no differences in hepatic VLDL-TG production or intestinal [3H]TG uptake...

Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL

Studies in humans and mice have shown that increased expression of apolipoprotein C-I (apoC-I) results in combined hyperlipidemia with a more pronounced effect on triglycerides (TGs) compared with total cholesterol (TC). The aim of this study was to elucidate the main reason for this effect using human apoC-I-expressing (APOC1) mice. Moderate...

Free and total urinary 2-butoxyacetic acid following dermal and inhalation exposure to 2-butoxyethanol in human volunteers

Objectives: To assess excretion kinetics of free and total (free + conjugated) 2-butoxyacetic acid (BAA) following dermal and inhalation exposure to butoxyethanol (BE). Methods: Six male volunteers were derma lly exposed for 4 h to a 50% aqueous solution of BE on an area of 40 cm2 of the volar forearm. Six other male volunteers were exposed by...

Retrospective detection of exposure to nerve agents: Analysis of phosphofluoridates originating from fluoride-induced rectivation of phospylated BuChE

The utility was explored of a new approach to detect retrospectively exposure to nerve agents by means of conversion of the inhibitor moiety bound to the active site of the enzyme BuChE in plasma with fluoride ions into a phosphofluoridate which is subsequently analyzed by means of gas chromatography (GC). This quantifies ≥0.01% inhibition of...

The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis

The VLDL receptor (VLDLr) is involved in tissue delivery of VLDL-triglyceride (TG)-derived FFA by facilitating the expression of lipoprotein lipase (LPL). However, vldlr-/- mice do not show altered plasma lipoprotein levels, despite reduced LPL expression. Because LPL activity is crucial in postprandial lipid metabolism, we investigated whether...

Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged, or had no effect on lysis in vitro. The...

Age-related accumulation of the advanced glycation endproduct pentosidine in human articular cartilage aggrecan: The use of pentosidine levels as a quantitative measure of protein turnover

During aging, non-enzymatic glycation results in the formation and accumulation of the advanced glycation endproduct pentosidine in long-lived proteins, such as articular cartilage collagen. In the present study, we investigated whether pentosidine accumulation also occurs in cartilage aggrecan. Furthermore, pentosidine levels in aggrecan...

Exposure to fungicides in fruit growing: Re-entry time as a predictor for dermal exposure

As part of a European Concerted Action on Male Reproduction Capability an exposure assessment survey was conducted among seasonal workers in the fruit growing sector in the Netherlands. Dermal exposure to the fungicides captan and tolylfluanid was measured using cotton gloves (12 persons) and skin pads on several body parts (12 persons). In...

In vitro stabililty of a tissue-type plasminogen activator mutant, BM 06.022, in human plasma

BM 06.022 is a non-glycosylated mutant of human tissue-type plasminogen activator (t-PA) comprising only the kringle-2 and proteinase domains. The in vivo half-life of BM 06.022 antigen is 4- to 5-fold longer than that of t-PA antigen. The in vitro half-life of the activity of BM 06.022 at therapeutic concentrations in plasma is shorter than...