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J Hoogstraate

Publications and source records attributed to J Hoogstraate.

5 recordsLinked to original sources
PubMed2005

Pre-clinical pharmacokinetics of the cyclooxygenase-inhibiting nitric oxide donor (CINOD) AZD3582.

The pre-clinical pharmacokinetics of AZD3582 (4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate) and its primary metabolites (naproxen and nitrate) were evaluated. AZD3582 had intermediate and passive intestinal permeability (40 times lower than for naproxen), high systemic plasma clearance (CL), substantial gastrointestinal hydrolysis, intermediate volume of distribution (Vss; >or=3.4 L kg-1) and half-life (t1/2; 7 h), negligible plasma protein binding (approximately 0.1%), low/intermediate oral uptake (>or=13% as intact substance) and low and varying oral bioavailability (mean 1.4% in minipigs and 3.9% in dogs). Following administration of therapeutically relevant oral doses, plasma concentrations of AZD3582 were very low ( 40 h in rats, minipigs and dogs, respectively. The Vss and CL for naproxen were small. Plasma protein binding was extensive, and saturation was observed within the therapeutic dose and concentration range. Intake of food prolonged the systemic absorption of naproxen in the minipig. The pharmacokinetics of naproxen did not show apparent time- or gender-related dependency. Following oral dosing of [3H]-, [14C]- and [15N]-AZD3582, most [14C]- and [3H]-activity was excreted in urine and expired air, respectively. Seventeen per cent of [15N] was recovered in minipig urine as [15N]-nitrate. About 30% of [3H]-activity (naproxen and/or naproxen-related metabolites) was excreted in bile and re-absorbed. Concentrations of [14C]-activity (nitrooxy-butyl group and/or its metabolites) in milk were higher than in plasma and [3H]-activity in milk. [3H]- and [14C]-excretion data indicated that intact AZD3582 was not excreted in urine, bile or milk to a significant extent. There was no apparent consistency between tissue distribution of [14C]- and [3H]-activity in the rat, which suggests rapid and extensive metabolism of extravascularly distributed AZD3582. A substantial increase of plasma nitrate levels was found after single and repeated oral doses of AZD3582 in the minipig. No inhibition or induction of CYP450 was found.

Animals↗
PubMed2004

Pharmacokinetics of two major hydroxylated polychlorinated biphenyl metabolites with specific retention in rat blood.

1. Hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) are, depending on their structure, strongly retained in mammalian, fish and bird blood. This is due to strong, though reversible, binding to the thyroxine binding and transporting protein transthyretin. 2,3,3',4',5-Pentachloro-4-biphenylol (4-OH-CB 107) and 2,2',3,4',5,5',6-heptachloro-4-biphenylol (4-OH-CB 187) are two of five major OH-PCB congeners in human plasma. 2. The relative amounts of OH-PCB congeners vary between species and also between human populations, in spite of similar PCB congener patterns, and may depend on different pharmacokinetic parameters of the OH-PCBs. In the present study, the pharmacokinetic parameters of 4-OH-CB 107 and 4-OH-CB 187 were determined in the rat after a single intravenous dose of 1 micromol kg(-1). Plasma samples were analysed by gas chromatography/mass spectrometry. 3. 4-OH-CB 107 had a half-life of 3.8 days; 4-OH-CB 187 had a half-life of 15 days. Volumes of distribution were 0.07 and 0.11 l kg(-1), respectively; clearances (ml h(-1)) were 0.67 and 0.22, respectively; and the areas under the curve were estimated as approximately 1500 and 4450 nmol h ml(-1). 4. The pharmacokinetic parameters thus determined help to explain the observed differences in the relative amounts of OH-PCBs in humans and other mammals exposed to environmental PCBs.

Animals↗
PubMed2001

Sequencing and tissue distribution of the canine MRP2 gene compared with MRP1 and MDR1.

The effects of xenobiotic drugs and toxic compounds depend largely on their kinetic properties, which can be influenced by transmembrane drug transporters like MDR1/P-glycoprotein and the drug-conjugate transporters multidrug resistance protein (MRP) 1 and 2. As the dog is a preferential species used in the pharmacological and toxicological evaluation of new drugs, we sequenced the canine MRP2 cDNA and investigated its expression in various canine tissues compared with the related transporters MRP1 and P-glycoprotein. The tissue distribution pattern of these ABC-transporters differs partially from the distribution described in humans. So we found relatively high renal and low hepatic canine MRP2 expression levels, relatively high hepatic canine MRP1 expression levels, and quite high levels of MRP1 and P-glycoprotein in the dog brain. The knowledge of the tissue distribution pattern of these transporters will aid to interpret pharmacokinetic and toxicokinetic data gained from dog studies and to extrapolate them to humans.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2001

Evaluation of a vincristine resistant Caco-2 cell line for use in a calcein AM extrusion screening assay for P-glycoprotein interaction.

AIM: To develop a fast fluorometric screening assay based on vincristine resistant Caco-2 cells (Caco-2VCR) in order to elucidate potential P-glycoprotein (Pgp) interactions of compounds, and to characterise Caco-2VCR cells with regard to their expression of the efflux transporters Pgp, MRP1 and MRP2. METHODS: We applied the Caco-2VCR cells to a 96-well plate-based calcein AM extrusion assay. The Caco-2VCR cells were cultured as monolayers and incubated with calcein AM with/without addition of Pgp modulators. Fourteen known Pgp modulators were tested in the assay (chloropromazine, cyclosporin A, domperidone, digoxin, ivermectin, ketoconazole, loperamide, metoprolol, propranolol, progesterone, quinidine, quinine, verapamil and vincristine). For each compound an EC50 value was calculated. Protein and mRNA levels of the efflux transporters were analysed by Western blot and polymerase chain reaction techniques. RESULTS: All compounds with the exception of digoxin displayed increased calcein levels. Protein and mRNA analysis showed increased levels of Pgp after vincristine exposure, while expression of the efflux transporters MRP1 and MRP2 remained unchanged. CONCLUSIONS: The calcein AM extrusion assay applied to Caco-2VCR cells can be a valuable tool as a screening assay for new compounds and their potential interaction with P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗