Pharmacokinetics of Dolasetron after Oral and Intravenous Administration of Dolasetron Mesylate in Healthy Volunteers and Patients with Hepatic Dysfunction

Abstract

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child-Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child-Pugh class B or C1; group III). Single 150-mg doses of dolasetron mesylate were administered intravenously and orally, with a 7-day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration-time curve (AUC), or elimination half-life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (C(lapp)) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, C(lapp) of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Cl(app) of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function.

Carbonyl reduction of naltrexone and dolasetron by oxidoreductases isolated from human liver cytosol

“…For dolasetron the participation of CR in enzymatic reduction led to an extremely rapid disappearance of the parent drug and ketone/alcohol ratios close to zero from 1 h after intravenous infusion as well as throughout after oral dosing. Moderate or severe hepatic impairment allowed a small fraction of oral dolasetron to escape first-pass carbonyl reduction (Stubbs et al 1997). The occurrence of CR in the majority of human tissues (Wirth & Wermuth 1992) enables them to participate in (2000).…”

“…Dolasetron belongs to the group of serotonin (5-HT 3 ) receptor antagonists used as adjuvants in cancer chemo-or radiotherapy due to their potent antiemetic effect (Perez 1998). It is even more efficiently reduced in man in-vivo than is naltrexone, such that the original compound is hardly detectable in plasma after oral administration to healthy subjects, while after intravenous infusion it mostly becomes undetectable within 2 h (Boxenbaum et al 1992(Boxenbaum et al , 1993Stubbs et al 1997). The chiral alcohol resulting from carbonyl reduction, reduced dolasetron or hydrodolasetron (Figure 1), proved to be about 40 times more potent than dolasetron as a 5-HT 3 receptor antagonist, such that dolasetron may be regarded as a prodrug (Boeijinga et al 1992).…”

“…The chiral alcohol resulting from carbonyl reduction, reduced dolasetron or hydrodolasetron (Figure 1), proved to be about 40 times more potent than dolasetron as a 5-HT 3 receptor antagonist, such that dolasetron may be regarded as a prodrug (Boeijinga et al 1992). In healthy subjects given dolasetron orally or intravenously, the elimination half-life of reduced dolasetron was around 7-8 h (Boxenbaum et al 1992(Boxenbaum et al , 1993Stubbs et al 1997). Enantiomer analysis revealed stereoselective reduction with 95% (R)-enantiomer in reduced dolasetron excreted in human urine.…”

A review of dolasetron as management of nausea and vomiting in cancer patients

“…9 Although liver dysfunction can impair the metabolism of dolasetron, dosage reductions are not required for patients with hepatic or renal impairment. 10,11 In comparing dolasetron's pharmacokinetics with those of other 5 -HT 3 ± receptor antagonists, dolasetron was observed to have a higher bioavailability (76% ) and shorter time to maximum concentration (40 minutes ) compared with ondansetron ( 56 ± 71% and 1 ±2.1 hours, respectively ) and granisetron ( 60% and 2 hours, respectively ). In addition, dolasetron exhibits the longest half -life ( 7± 8 hours ) (ondansetron, 2.5 ±5 hours; granisetron, 4 ± 6 hours ) .…”

Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats

“…However, in human patients with renal impairment dose reduction is not recommended. 6,7 Furthermore, the safety profile of this 5-HT 3 antagonist is considered excellent in humans with adverse effects (headache, constipation or diarrhea in humans) being mild and transient. 1,3 Anecdotally, no significant side effects have been reported in feline patients.…”