Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dolasetron mesilate (Anzemet) ((2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl-1 H-indole-3-carboxylate monomethane-sulfonate) is a 5-HT3 receptor antagonist, which is in development for the treatment of chemotherapy-induced emesis. The ketone moiety of dolasetron is rapidly reduced by carbonyl reductase to form an alcohol, reduced dolasetron (red-dolasetron), which is the major pharmacologically active metabolite in humans. The pharmacokinetics of dolasetron and red-dolasetron were compared in dog, after single intravenous (i.v.) (2 mg/kg) and oral (p.o.) (5 mg/kg) administration of [14C]dolasetron or [14C]red-dolasetron. Pharmacokinetic parameters of dolasetron showed a terminal elimination half-life (t1/2) of 0.1 h, total body plasma clearance (Cltot) of around 109 mL/min/kg, apparent volume of distribution (aVd beta) of 0.83 L/kg, and bioavailability (F) of 7%. Pharmacokinetic parameters of red-dolasetron, calculated after dolasetron or red-dolasetron administration, were very similar. The t1/2 was around 4.0 h, Cltot 25 mL/min/kg, aVd beta 8.5 L/kg, and F around 100%. The apparent first-order formation rate constant (ki) of red-dolasetron was 7 h-1, which was similar to the first-order elimination rate constant (kel) of dolasetron. Cmax of red-dolasetron was similar, after po administration of either compound, but the median Tmax was 0.33 h after dolasetron, compared with 1.5 h after red-dolasetron. The first-order absorption rate constants (ka) of dolasetron and red-dolasetron were 14 h-1 and 2 h-1, respectively. Dolasetron transport across Caco-2 cell monolayers was also higher than that of red-dolasetron. Thus dolasetron was more quickly absorbed than red-dolasetron, and its administration led to the more rapid appearance of red-dolasetron in plasma. There appears to be no advantage in the direct administration of the metabolite, especially as in humans oral administration of dolasetron, 30 min before chemotherapy, has been shown to be effective in preventing emesis.
 ...
PMID:Comparison of the pharmacokinetics of dolasetron and its major active metabolite, reduced dolasetron, in dog. 881 90

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5-HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half-life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vd beta) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the (+)-enantiomer of the reduced metabolite, which accounted for 25.35% (+/- 7.79%) and 18.88% (+/- 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high-dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.
 ...
PMID:Pharmacokinetics of single intravenous and oral doses of dolasetron mesylate in healthy elderly volunteers. 893 Jul 77

1. Dolasetron (Anzemet) is a potent and selective 5-HT3 receptor antagonist which is rapidly and extensively reduced to yield its major pharmacologically active metabolite, reduced dolasetron (RD). RD is further metabolized by CYP450 enzymes as well as undergoing renal excretion. As both in vitro and in vivo data on RD were available from animals and man, two approaches to predict the human pharmacokinetic parameters of RD were assessed. 2. First, in vitro studies, using liver microsomes from animal species and man, were undertaken to measure Vmax and K(m) and to assess the intrinsic clearance (CLint). With appropriate liver weight and liver blood flow scaling factors the predicted in vivo metabolic clearance (CLm-pred) was calculated. Human CLm-pred was underestimated by a factor of 5 when it was calculated using the above scaling factors. As, in a prospective study, the observed human in vivo metabolic clearance (CLm-obs) is unknown, CLm-pred was substituted into the least-squares correlation equation obtained from a plot of CLm-pred against CLm-obs' using animal data. The estimate of human CLm-obs was improved as it was only underestimated by a factor of 1.5. 3. Second, allometric scaling of in vivo animal pharmacokinetic data, using body weight, was performed to predict pharmacokinetic parameters in man. Good predictions of human pharmacokinetic parameters of RD were obtained for plasma clearance (1.7 l/min predicted versus 1.61/min observed), half-life (6.0 h predicted versus 5.6 h observed), and volume of distribution (860.91 predicted versus 770.41 observed). 4. The integration of in vitro metabolic data from microsomes gave similar results to conventional allometric scaling, whereas the normalization of clearance by brain weight resulted in an approximately three-fold underestimation of human clearance. 5. For RD, a drug that is eliminated by both renal and metabolic clearance, retrospective conventional allometric scaling allowed accurate prediction of pharmacokinetic parameters in man, whereas in vitro-in vivo scaling resulted in an underestimation of in vivo CLm. Although these results are somewhat at variance, ideally both scaling methods should be applied to improve the prediction of human pharmacokinetic parameters.
 ...
PMID:Prediction of the pharmacokinetic parameters of reduced-dolasetron in man using in vitro-in vivo and interspecies allometric scaling. 905 32

Nausea and vomiting continue to rank as important side effects for cancer patients receiving chemotherapy. The class of drugs known as the 5-HT3 receptor antagonists have become widely used for chemotherapy-induced nausea and vomiting, and are considered a standard part of care for moderately- and highly-emetogenic chemotherapy in combination with corticosteroids. Ondansetron (Zofran, Glaxo Wellcome), granisetron (Kytril, SmithKline Beecham) and dolasetron (Anzemet, Hoechst Marion Roussel) are commercially available in the US. Intravenous forms of all three drugs have demonstrated efficacy in preventing acute (< or = 24 h following chemotherapy) nausea and emesis due to moderately- and highly-emetogenic chemotherapy. Oral forms of the drugs have been shown to be effective in prevention of nausea and emesis due to moderately-emetogenic chemotherapy. More recently, oral 5-HT3 receptor antagonists have demonstrated efficacy in the prevention of nausea and vomiting due to highly-emetogenic chemotherapy as well. Comparative trials between the three agents have shown no clinically important differences in outcome and they should be considered clinically equivalent. Optimal oral anti-emetic regimens for high-dose chemotherapy with bone marrow or stem cell transplantation remain to be determined and future oral studies should target this population. In general, the decision of which 5-HT3 receptor antagonist to select for formulary inclusion should be based on the dose of anti-emetic used and the acquisition cost of the agents being compared. The oral route should be used whenever possible.
 ...
PMID:Advances in use of the 5-HT3 receptor antagonists. 1124 43