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E Snoeck

Publications and source records attributed to E Snoeck.

24 records · Page 2Linked to original sources
PubMed1994

Plasma protein binding of risperidone and its distribution in blood.

The plasma protein binding of the new antipsychotic risperidone and of its active metabolite 9-hydroxy-risperidone was studied in vitro by equilibrium dialysis. Risperidone was 90.0% bound in human plasma, 88.2% in rat plasma and 91.7% in dog plasma. The protein binding of 9-hydroxy-risperidone was lower and averaged 77.4% in human plasma, 74.7% in rat plasma and 79.7% in dog plasma. In human plasma, the protein binding of risperidone was independent of the drug concentration up to 200 ng/ml. The binding of risperidone increased at higher pH values. Risperidone was bound to both albumin and alpha 1-acid glycoprotein. The plasma protein binding of risperidone and 9-hydroxy-risperidone in the elderly was not significantly different from that in young subjects. Plasma protein binding differences between patients with hepatic or renal impairment and healthy subjects were either not significant or rather small. The blood to plasma concentration ratio of risperidone averaged 0.67 in man, 0.51 in dogs and 0.78 in rats. Displacement interactions of risperidone and 9-hydroxy-risperidone with other drugs were minimal.

Adult↗
PubMed1994

The pharmacokinetics of risperidone in humans: a summary.

Risperidone is rapidly and completely absorbed after oral administration; less than 1% is excreted unchanged in the feces. The principal metabolite was found to be 9-hydroxyrisperidone. Hydroxylation of risperidone is subject to the same genetic polymorphism as debrisoquine and dextromethorphan. In poor metabolizers the half-life of risperidone was about 19 hours compared with about 3 hours in extensive metabolizers. However, becuase the pharmacology of 9-hydroxyrisperidone is very similar to that of risperidone, the half-life for the "active fraction" (risperidone +9-hydroxyrisperidone) was found to be approximately 20 hours in extensive and poor metabolizers. We found that risperidone exhibited linear elimination kinetics and that steady state was reached within 1 day for risperidone and within 5 days for the active fraction.

Aged↗
PubMed1990

New non-steroidal aromatase inhibitors: focus on R76713.

R76713 is a novel triazole derivative which selectively blocks the cytochrome P450-dependent aromatase. In human placental microsomes, in FSH-stimulated rat and human granulosa cells and in human adipose stromal cells, 50% inhibition of estradiol biosynthesis was obtained at drug concentrations of 2-10 nM. In PMSG-injected female rats, R76713 lowered plasma estradiol levels by 50 and 90% 2 h after single oral doses of 0.005 and 0.05 mg/kg respectively. After 1 mg/kg, estradiol levels were suppressed by 90% for 16 h. In male cynomolgus monkeys, R76713 dose-dependently (0.03-10 micrograms/kg) inhibited peripheral aromatization with an ED50 of 0.13 microgram/kg without altering metabolic clearance rates and conversion ratios. In vitro R76713 had no effect on other P450-dependent steroidogenic enzymes up to 1000 nM at least. In rats, LHRH-, ACTH- and sodium-deprived diet stimulated plasma testosterone, corticosterone and aldosterone levels were not modified 2 h after single oral administrations of R76713 (up to 20 mg/kg). Furthermore, R76713 did not show any in vitro or in vivo estrogenic or antiestrogenic property. R76713 also induced regression of DMBA-induced mammary tumors after daily oral administration of 1 mg/kg b.i.d. In male volunteers (n = 4), a single oral dose of 5 and 10 mg lowered median plasma estradiol levels from 70 pM to the detection limit of the assay (40 pM) 4, 8 and 24 h after intake whereas no changes were detected after placebo administration. In premenopausal women (n = 15), receiving a single oral dose of 20 mg, median plasma estradiol levels decreased from 389 pM (before) to 168, 133 and 147 pM, 4, 8 and 24 h after intake whereas they remained above 420 pM after placebo (n = 7).

Animals↗
PubMed1990

R 75251, a new inhibitor of steroid biosynthesis.

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Pharmacokinetic-pharmacodynamic relationships in phase I/phase II of drug development.

Early investigation of pharmacokinetic-pharmacodynamic relationships in Phase I/II may facilitate the further clinical development of a new drug. Although some pharmacology assessments in Phase I are often only surrogates for the therapeutic effect, PK-PD modelling of those effects provides in general crucial information on the drug's potency in vivo. A mathematical PK-PD expression allows explorative simulations on the rate of onset of drug action, on the intensity and duration of the effects for doses in future clinical trials, or in situations of altered drug kinetics. Furthermore, understanding of the PK-PD relationship early on in drug development may anticipate unnecessary exposure of human subjects to inappropriate drug doses or trials.

Animals↗