Biotransformation /is/ hepatic and complete, mainly to the active metabolite hydrodolasetron (by means of the ubiquitous enzyme, carbonyl reductase). Further hydroxylation is mediated by cytochrome P450 CYP2D6 and further N-oxidation by both CYP3A and flavin monooxygenase.
The metabolism of dolasetron mesylate was studied in six healthy male volunteers who were given a single 300 mg oral dose of [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in the urine and 25% in the feces. Metabolites were quantitated in urine samples taken up to 36 hr post-dose. Reduced dolasetron (RD) accounted for 17-54% of the dose in urine. Hydroxylated metabolites of RD made up no more than 9% of the dose in urine. Most of the remaining urinary radioactivity consisted of conjugated metabolites of RD and hydroxy RD. Hydrolysis of selected urine samples showed that the glucuronide of RD was the most abundant conjugate in urine. A small percentage of the dose (< 1%) in urine was identified as the N-oxide of RD. Analysis of urine samples by chiral HPLC indicated that the R(+):S(-) ratio of RD was approximately 9:1.
The initial step in the metabolism of dolasetron or MDL 73,147EF [(2 alpha, 6 alpha, 8 alpha, 9a beta)-octahydro-3-oxo-2,6-methano-2H- quinolizin-8-yl 1H-indol-3-carboxylate, monomethanesulfonate] is the reduction of the prochiral carbonyl group to give a chiral secondary alcohol "reduced dolasetron." An HPLC method, using a chiral column to separate reduced dolasetron enantiomers, has been developed and used to measure enantiomers in urine of rats, dogs, and humans after dolasetron administration. In all cases, the reduction was enantioselective for the (+)-(R)-enantiomer, although the dog showed lower stereoselectivity, especially after iv administration. An approximate enantiomeric ratio (+/-) of 90:10 was found in rat and human urine. The contribution of further metabolism to this enantiomeric ratio was considered small as preliminary studies showed that oxidation of the enantiomeric alcohols by human liver microsomes demonstrated only minor stereoselectivity. Further evidence for the role of stereoselective reduction in man was obtained from in vitro studies, where dolasetron was incubated with human whole blood. The enantiomeric composition of reduced dolasetron formed in human whole blood was the same as that found in human urine after administration of dolasetron. Enantioselectivity was not due to differences in the absorption, distribution, metabolism, or excretion of enantiomers, as iv or oral administration of rac-reduced dolasetron to rats and dogs lead to the recovery, in urine, of essentially the same enantiomeric composition as the dose administered. It is fortuitous that the (+)-(R)-enantiomer is predominantly formed by carbonyl reductase, as it is the more active compound.
The 5-HT3 receptor antagonists have been linked to occasional instances of serum enzyme elevations during therapy, but these are generally mild and asymptomatic, resolving rapidly. Because they are used at the time of surgery and with chemotherapy, instances of liver injury arising after their use have been reported, but other drugs or factors may have played a role in the published cases. The rate of serum enzyme elevations with 5-HT3 receptor antagonist therapy has ranged from 1% to 8% and has generally been no greater than that observed with placebo therapy. While moderate serum enzyme elevations during 5-HT3 receptor antagonist therapy have been described, there have been have been only rare and isolated reports of clinically apparent acute liver injury with jaundice attributed to these agents. The onset of injury has been within 1 to 2 weeks of exposure and the pattern of injury hepatocellular and without immunoallergic or autoimmune features. Instances of recurrence after re-exposure have been published. No instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to the 5-HT3 receptor antagonists.
Alosetron likelihood score: D (possible cause of clinically apparent liver injury).
Dolasetron likelihood score: E (unlikely cause of clinically apparent liver injury).
Granisetron likelihood score: E (unlikely cause of clinically apparent liver injury).
Ondansetron likelihood score: D (possible cause of clinically apparent liver injury).
Palonosetron likelihood score: E (unlikely cause of clinically apparent liver injury).
Concurrent use of cimetidine, which is a nonselective cytochrome P450 enzyme inhibitor, with dolasetron for 7 days has been found to result in a 24% increase in hydrodolasetron blood concentrations.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
静脉注射多拉塞曲林和atenolol同时使用已被发现会使多拉塞曲林的清除率降低27%。
Concurrent use of intravenous dolasetron and atenolol has been found to result in a 27% decrease in clearance hydrodolasetron.
Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服多拉塞曲酮吸收良好，但由于迅速且完全代谢为羟基多拉塞曲酮，母药在血浆中很少被检测到。
Orally-administered dolasetron is well absorbed, but the parent drug is rarely detected in plasma due to rapid and complete metabolism to hydrodolasetron.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服多拉赛曲静脉注射溶液和片剂具有生物等效性。
Orally-administered dolasetron intravenous solution and tablets are bioequivalent.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服多拉赛龙的明显绝对生物利用度大约为75%。食物不会影响口服多拉赛龙的生物利用度。
The apparent absolute bioavailability of oral dolasetron is approximately 75%. Food does not affect the bioavailability of dolasetron taken by mouth.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服给药后达到峰血浆浓度的时间/对于羟多拉佐龙/大约是1小时，静脉注射后/是/0.6小时。
Time to peak plasma concentration /for hydrodolasetron/ following oral administration /was/ approximately 1 hour and following intravenous injection /was/ 0.6 hours.
