Systemic exposure of vinpocetine in pregnant Sprague Dawley rats following repeated oral exposure: An investigation of fetal transfer

Abstract

Vinpocetine is being used worldwide by people of all ages, including pregnant women, for its purported multiple health benefits. However, limited data is available addressing the safety/toxicity of vinpocetine. The National Toxicology Program conducted studies to examine potential effects of vinpocetine on the developing rat. Disposition data is helpful to put the fetal findings into context and provide information on the potential risk for humans. The current study reports the systemic exposure and toxicokinetic (TK) parameters of vinpocetine and metabolite, apovincaminic acid (AVA), in pregnant Harlan Sprague Dawley rats, fetuses and amniotic fluid following oral gavage exposure of dams to 5 and 20mg/kg vinpocetine from gestational day 6 to 18. Vinpocetine was absorbed rapidly in dams with a maximum plasma concentration (C) reaching ≤1.37h. Predicted C and area under the concentration versus time curve (AUC) increased less than proportionally to the dose. Vinpocetine was rapidly distributed to the peripheral compartment. More importantly, significant transfer of vinpocetine from dam to fetuses was observed with fetal C and AUC≥55% of dams. Vinpocetine was cleared rapidly from dam plasma with an elimination half-life of ≤4.02h with no apparent dose-related effect. Vinpocetine was rapidly and highly metabolized to AVA with AVA plasma levels in dams ≥2.7-fold higher than vinpocetine, although in the fetuses, AVA levels were much lower than vinpocetine. Comparison of current rat data with literature human data demonstrates that systemic exposure to vinpocetine in rats following repeated exposure to 5mg/kg is similar to that following a single human relevant dose of 10mg suggesting that the findings from the toxicology study may be relevant to humans.

Embryo‐fetal development studies with the dietary supplement vinpocetine in the rat and rabbit

“…However, in contrast to the rats, there appears to be a species-specific difference in response as the increase in post-implantation loss in the rabbits was limited to the 300 mg/kg group, the magnitude of the response was diminished (20% in the rabbit 300 mg/kg group vs. 83% in the rat 60 mg/kg group) and was not significantly increased compared to the controls. We have previously demonstrated significant fetal transfer of vinpocetine following repeat administration of vinpocetine (5 and 20 mg/kg) in pregnant rats from GD 6 to 18, with fetal C max and AUC values ≥ 55% of dams (Waidyanatha et al, 2017). Additionally, this study identified the rapid metabolism of vinpocetine to its main metabolite, AVA, in the dam, with AVA levels ≥ 2.7-fold higher than vinpocetine.…”

“…However, AVA levels in the fetus were much lower than vinpocetine. The dose-normalized plasma levels of vinpocetine and AVA in rabbits in the present study at 1 and 2 h following administration of 25 mg/kg vinpocetine on GD 19 was compared with the corresponding data from the rat study (Waidyanatha et al, 2017) (Figure 4). The dose-normalized vinpocetine levels were 7- to 15-fold higher in the rats compared to the rabbits (Figure 4A).…”

“…Published human systemic exposure data are limited, but have shown a C max of 25.2 and 64.3 ng/mL and an AUC of 249.4 and 519.7 ng*h/mL following a single dose of 10 mg (Elbary, 2002; Karshoum, 2013). A comparison of systemic exposure where VSDs were noted in rats (5 mg/kg) to that at suggested doses in humans (single 10 mg dose), results in exposure multiples of ≤14 and ≤9 for C max and AUC, respectively (Waidyanatha, 2017). These dose comparisons suggest that exposure to vinpocetine in rats following a repeated 5 mg/kg dose is similar to that following a single 10 mg dose in humans.…”

“…Does (n=4) were randomly selected from all groups for blood collection. Limited toxicokinetic data on vinpocetine in rabbits from the literature demonstrated that plasma C max is reached between 1 and 2 h and hence these time points were selected to evaluate plasma levels of vinpocetine and apovincaminic acid (AVA) in rabbits and compared to previously published rat data (Waidyanatha et al, 2017). Following vinpocetine administration on GD 19, blood was collected via the ear vein using K 3 EDTA at 1 and 2 h. Immediately following collection, tubes were mixed gently and placed on wet ice.…”

“…A method previously reported for rat plasma (Waidyanatha et al, 2017) using protein precipitation followed by liquid chromatography-mass spectrometry was cross validated to rabbit plasma to quantitate vinpocetine and apovincaminic acid (AVA) over the concentration range 0.5 to 100 ng/mL. This method was linear (≥ 0.99), accurate (% relative error, -6.4 to 9.7) and precise (% relative standard deviation, 1.3 to 12.3) for both vinpocetine and AVA in rabbit plasma.…”