Pharmacokinetics of enzalutamide, an anti-prostate cancer drug, in rats

Abstract

We characterized the pharmacokinetics of enzalutamide, a novel anti-prostate cancer drug, in rats after intravenous and oral administration in the dose range 0.5-5 mg/kg. Tissue distribution, liver microsomal stability, and plasma protein binding were also examined. After intravenous injection, systemic clearance, volumes of distribution at steady state (Vss), and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 80.4-86.3 mL/h/kg, 1020-1250 mL/kg, and 9.13-10.6 h, respectively. Following oral administration, absolute oral bioavailability was 89.7 % and not dose-dependent. The recoveries of enzalutamide in urine and feces were 0.0620 and 2.04 %, respectively. Enzalutamide was distributed primarily in 10 tissues (brain, liver, kidneys, testis, heart, spleen, lungs, gut, muscle, and adipose) and tissue-to-plasma ratios of enzalutamide ranged from 0.406 (brain) to 10.2 (adipose tissue). Further, enzalutamide was stable in rat liver microsomes, and its plasma protein binding was 94.7 %. In conclusion, enzalutamide showed dose-independent pharmacokinetics at intravenous and oral doses of 0.5-5 mg/kg. Enzalutamide distributed primarily to 10 tissues and appeared to be eliminated primarily by metabolism.

Intravenous delivery of enzalutamide based on high drug loading multifunctional graphene oxide nanoparticles for castration-resistant prostate cancer therapy

“…The mice were kept at RT, and the relative humidity was maintained in the range of 35-50%. An in vivo assay was performed after the tumour reached approximately 100 mm 3 .…”

“…It could improve the efficacy of CRPC therapy via competitively inhibiting the interaction between androgen and AR. However, Enz has shown limited bioavailability via oral administration and increased systemic side effects when patients were exposed at high doses [3][4][5][6]. Therefore, new strategies to enhance the targeted delivery to reduce systemic side effects and improve bioavailability of Enz are urgently needed.…”

Dose considerations for anti-cancer drugs in metastatic prostate cancer

“…The cause of these low incident CNS‐type effects is uncertain although studies in rodents show that enzalutamide and its metabolites have CNS penetration . There is evidence that enzalutamide‐induced CNS effects are dose‐related and may be due to high systemic exposure.…”

“…54 The cause of these low incident CNS-type effects is uncertain although studies in rodents show that enzalutamide and its metabolites CRUMBAKER AND GURNEY | 1201 have CNS penetration. 55 There is evidence that enzalutamide-induced CNS effects are dose-related and may be due to high systemic exposure. In the phase I study, the maximum tolerated dose was 240 mg/day with dose-limiting toxicities of seizures, confusion and fatigue, prompting dose reduction.…”

Development and Clinical Effectiveness of Antiandrogens in the Treatment of Advanced Prostate Cancer

“…В сравнительном доклиническом исследовании на моделях КРРПЖ энзалутамид подавлял связывание АР с ДНК и синтез ПСА и РНК, в то время как бикалутамид стимулировал эти процессы, а поскольку ПСА является геном-мишенью для АР и его синтез является маркером активности АР, то появилось теоретическое обоснование и последующее экспериментальное и клиническое подтверждение для возможности получения дополнительного клинического успеха [13][14][15][16][17][18][19].…”