Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

Abstract

ABSTRACT. Veratramine, a major alkaloid from Veratrum nigrum L., has distinct anti-tumor and antihypertension effects. Our previous study indicated that veratramine had severe toxicity toward male rats. In order to elucidate the underling mechanism, in vivo pharmacokinetic experiments and in vitro mechanistic studies have been conducted. Veratramine was administrated to male and female rats intravenously via the jugular vein at a dose of 50 μg/kg or orally via gavage at 20 mg/kg. As a result, significant pharmacokinetic differences were observed between male and female rats after oral administration with much lower concentrations of veratramine and 7-hydroxyl-veratramine and higher concentrations of veratramine-3-O-sulfate found in the plasma and urine of female rats. The absolute bioavailability of veratramine was 0.9% in female rats and 22.5% in male rats. Further experiments of veratramine on Caco-2 cell monolayer model and in vitro incubation with GI content or rat intestinal subcellular fractions demonstrated that its efficient passive diffusion mediated absorption with minimal intestinal metabolism, suggesting no gender-related difference during its absorption process. When veratramine was incubated with male or female rat liver microsomes/cytosols, significant malepredominant formation of 7-hydroxyl-veratramine and female-predominant formation of veratramine-3-O-sulfate were observed. In conclusion, the significant gender-dependent hepatic metabolism of veratramine could be the major contributor to its gender-dependent pharmacokinetics.

Pharmacokinetics and enterohepatic circulation of jervine, an antitumor steroidal alkaloid from Veratrum nigrum in rats

“…The appearance of enterohepatic circulation, equivalent to a "autologous administration" process, is bound to improve the oral bioavailability, increase the probability of drug-drug interaction (DDI), and even exhibit potential toxicity. In our study, the oral absolute bioavailability of jervine was 60.0%, which was much higher than that of veratramine (22.5%) [10] or cyclopamine (33%) [15]. It might be due to the enterohepatic circulation.…”

“…Similar to other veratrum alkaloids [3,10,15], jervine reached the first peak rapidly (<2 h), indicating that jervine was absorbed rapidly from the gastrointestinal tract. The fast absorption may be related to the proper lipophilicity of steroidal alkaloids.…”

“…With regard to the phenomenon of the second peak, some studies have shown that it is associated with enterohepatic circulation [16], and suggested that it is caused by the different absorption mechanisms of drugs in the gastrointestinal tract [17]. Notably, the phenomenon of enterohepatic circulation was first observed in jervine, but not other veratrum alkaloids like veratramine [3,10] or cyclopamine [15]. The specific pharmacokinetic behavior of jervine may be related to its particular structure.…”

“…Therefore, the characterization of jervine pharmacokinetic profile is essential for the evaluation of its efficacy, safety, and potential interactions with other drugs. Due to the narrow therapeutic index, a variety of veratrum alkaloids have been investigated for their pharmacokinetic characteristics [10]. However, up to now, few studies have evaluated the pharmacokinetic profile of monomer of jervine.…”

Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies

“…The IV route was chosen for this initial pharmacokinetic study because its pharmacokinetic parameters would not be contaminated by an absorption phase and/or first-pass metabolism that affects the outcome of drug treatment administered orally. Only male rats were used to minimize factors that may contribute to sexbased differences in metabolism and pharmacokinetics (36,37). Male and female rats could metabolize MyoNovin to different extents due sex dependent hepatic metabolism.…”