Ondansetron Clinical Pharmacokinetics

Abstract

Ondansetron is a potent and highly selective serotonin 5-HT3-receptor antagonist which has demonstrated important antiemetic activity and good tolerability in the prevention of chemotherapy-induced nausea and vomiting. Ondansetron is completely and rapidly absorbed from the gastrointestinal tract after oral administration, and does not accumulate with repeated oral administration. Owing to hepatic first-pass metabolism, its bioavailability is only about 60% compared with ondansetron administered by infusion over 15 minutes. Bioavailability is slightly increased when administered after a standard meal, and is not influenced by coadministration of antacids; a slightly enhanced bioavailability has been observed in patients with cancer. Since the time to reach peak concentration is 0.5 to 2 hours after oral ingestion, the drug should be administered at least 30 minutes before chemotherapy. Possible alternative ways of administration of ondansetron include intramuscular, subcutaneous and rectal administration, and oral controlled-release formulations. Ondansetron is widely distributed (volume of distribution approximately 160L) and binds moderately (70 to 76%) to plasma proteins; the elimination half-life averages approximately 3.8 +/- 1 hours. Clearance occurs by hepatic metabolism (95%) rather than renal excretion. Metabolites do not play a role in the activity of the drug, and there is no evidence of genetic polymorphic metabolism. Although aging is associated with decreased clearance and increased bioavailability, dosage adjustments are not required for the elderly, and may be necessary only in patients with severe hepatic impairment. Chemotherapeutic agents do not seem to modify the pharmacokinetics of ondansetron. There remains the question of whether control of emesis is related to systemic availability of ondansetron and, in consequence, the optimal dose and schedule of ondansetron is still to be identified with certainty.

Ondansetrona oral na prevenção de náuseas e vômitos pós-operatórios

“…Noventa e cinco por cento da droga é metabolizada no fígado e eliminada via renal. Os metabólitos não são ativos 108 . A opção por via oral no pré-operatório requer a solução de três problemas: 1) Garantir níveis plasmáticos de ondansetrona adequados após a passagem hepática; 2) Garantir que estes níveis estejam presentes no pós-operatório imediato, e que não tenham decaído a ponto de se tornarem inefetivos;…”

“…Em voluntários normais, encontrou-se, após injeção intravenosa de 8 mg, pico de concentração plasmática entre 67,9 e 139,9 ng/mL, meia-vida de eliminação entre 2,7 e 5,8 h 119,120 e depuração plasmática entre 0,262 e 0,381 L/h/kg 108 . Após a administração oral de 8 mg, encontrou-se pico de concentração plasmática entre 22,0 e 48,4 ng/mL, e tempo máximo para pico de concentração plasmática entre 1,7 e 2,2h.…”

“…Após a administração oral de 8 mg, encontrou-se pico de concentração plasmática entre 22,0 e 48,4 ng/mL, e tempo máximo para pico de concentração plasmática entre 1,7 e 2,2h. A meia-vida de eliminação oscilou entre 2,4 e 5,8 h 119,120 , e a depuração plasmática de 0,249 a 0,403 L/h/kg 108 . Os picos de concentração plasmática tendem a ser mais elevados e a depuração mais lenta em idosos 108,120 e nas mulheres 108 .…”

“…Apesar de apresentar resultado mais eficaz que a metoclopramida 3,7,13,56,85,87,91,105 , o custo elevado das preparações intravenosas de ondansetrona tem ainda limitado sua utilização 81,106,107 . Assim, considerando as características farmacocinéticas favoráveis 108,109 , o menor custo e a conveniência da administração oral, busca-se, através deste estudo, avaliar a efetividade da ondansetrona oral na prevenção de NVPO. …”

Granisetron vs ondansetron: is it a question of duration of 5-HT3 receptor blockade?

“…Compelling data accumulated from cutaneous flare experiments in human volunteers demonstrate that, following a single infusion of granisetron, 40 mg kg 71 , the 5-HT 3 receptor-mediated axon flare reflex is significantly reduced for at least 24 h (Cooper et al, 1988;Upward et al, 1990). This contrasts with a 2.6-fold shorter duration of action after infusion with ondansetron, 8 and 16 mg (Sweetland et al, 1992) and is further supported by the longer plasma half-life of granisetron (about 10 h; Carmichael et al, 1989) compared with ondansetron (about 3.8 h; Roila and Del Favero, 1995). Furthermore, granisetron differs from the competitive antagonist ondansetron in that it displays insurmountable antagonism at vagal afferent 5-HT 3 receptors (Newberry et al, 1993), and it is this property that is thought to underlie the phenomenon that its pharmacodynamic half-life far exceeds its plasma half-life.…”