Systemic Exposure of Vinpocetine in Pregnant Sprague Dawley Rats Following Repeated Oral Exposure: An Investigation of Fetal Transfer

Suramya Waidyanatha, Heather Toy, Natalie South, Seth Gibbs, Esra Mutlu, Brian Burback, Barry S.McIntyre, and Natasha Catlin.
Toxicology and Applied Pharmacology (2018) DOI: https://doi.org/10.1016/j.taap.2017.11.011 PMID: 29155086

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Abstract

Vinpocetine is being used worldwide due to its purported benefits including treatment of cerebrovascular and cognitive disorders and claims of cognitive enhancement. Recent marketing promotes the use of vinpocetine for many other additional purported benefits, and hence, there is potential use of vinpocetine by people of all ages, including women of child bearing age and pregnant women. However, there is limited data in the current literature addressing the safety/toxicity of vinpocetine. The National Toxicology Program is conducting studies to examine potential effects of vinpocetine on the developing rat. Disposition and toxicokinetics (TK) data is helpful to put the fetal findings into context, and provide information on the potential risk for humans. Although there are some TK data for vinpocetine and its major metabolite, apovincaminic acid (AVA) in adult rodents in the literature following a single administration, there are no data following repeated administration and/or exposure in utero. The current study reports the systemic exposure and TK of vinpocetine and AVA in pregnant rats, fetuses and amniotic fluid following gavage exposure of dams to 5 and 20 mg/kg vinpocetine from gestational day (GD)6 to 18. Vinpocetine was absorbed rapidly in pregnant rats with a maximum plasma concentration reached £ 1.37h. Predicted maximum concentration (Cmax) increased less than proportionally to the dose (p = 0.0375). Area under the concentration versus time curve (AUC) increased 3.3-fold with a 4-fold increase in dose, although there was no significant difference between doses. Vinpocetine was rapidly distributed to the peripheral compartment. More importantly, significant transfer of vinpocetine from dam to fetuses was observed with fetal Cmax and AUC values ≥ 55% of dams. It was cleared rapidly from dam plasma with a half-life £ 4.02h with no apparent dose-related effect. Vinpocetine was rapidly and highly metabolized to AVA with AVA levels in dams ≥ 2.7-fold higher than vinpocetine, although in the fetus, the AVA levels were much lower than vinpocetine, itself. Comparison of our rat AUC and Cmax data with corresponding human data from the literature demonstrates that systemic exposure to vinpocetine in rats following repeated exposure to 5mg/kg is similar to that following a single dose of 10mg in humans.

Figures

Figure 1. Structure of vinpocetine and its major metabolite.

Structure of A) vinpocetine (apovincaminic acid ethyl ester) and B) its major metabolite, apovincaminic acid (apovincaminic-22-oic acid).

Figure 1 (127 KB)

Figure 2. Dam plasma concentration versus time profiles of vinpocetine.

Dam plasma concentration versus time profiles of vinpocetine following a single daily gavage dose of A) 5 mg/kg or B) 20 mg/kg vinpocetine in HSD rat dams from GD6 to GD18. One-compartmental model with first order input, first order output and 1/Ŷ2 weighting was used to fit the data.

Figure 2 (107 KB)

Figure 3. Dam plasma concentration versus time profiles of apovincaminic acid.

Dam plasma concentration versus time profiles of apovincaminic acid following a single daily gavage dose of A) 5 mg/kg or B) 20 mg/kg vinpocetine in HSD rat dams from GD6 to GD18. Data were analyzed using noncompartmental analysis.

Figure 3 (87 KB)

Figure 4. Fetus concentration versus time profiles of vinpocetine.

Fetus concentration versus time profiles of vinpocetine following a single daily gavage dose of A) 5 mg/kg or B) 20 mg/kg vinpocetine in HSD rat dams from GD6 to GD18. Data were analyzed using noncompartmental analysis.

Figure 4 (94 KB)

Figure 5. Fetus homogenate concentration versus time profiles of apovincaminic acid.

Fetus homogenate concentration versus time profiles of apovincaminic acid following a single daily gavage dose of A) 5 mg/kg or B) 20 mg/kg vinpocetine in HSD rat dams from GD6 to GD18. Data were analyzed using noncompartmental analysis.

Figure 5 (87 KB)

Figure 6. Comparison of dose-normalized A) Cmax and B) AUC∞ of vinpocetine.

Comparison of dose-normalized A) Cmax and B) AUC∞ of vinpocetine in dam plasma, amniotic fluid and fetus following a single daily gavage dose of vinpocetine in HSD rat dams from GD6 to GD18.

Figure 6 (372 KB)

Figure 7. Comparison of dose-normalized A) Cmax and B) AUC∞ of apovincaminic acid.

Comparison of dose-normalized A) Cmax and B) AUC∞ of apovincaminic acid in dam plasma, amniotic fluid and fetus following a single daily gavage dose of vinpocetine in HSD rat dams from GD6 to GD18.

Figure 7 (206 KB)

Tables

Table 1. Analytical method validationa and stability data for vinpocetine and apovincaminic acid.

Analytical method validationa and stability data for vinpocetine and apovincaminic acid in dam plasma, amniotic fluid, and fetal homogenate.

Table 1 (41 KB)

Table 2. Toxicokinetic parametersa for vinpocetine and apovincaminic acid in dam plasma.

Toxicokinetic parametersa for vinpocetine and apovincaminic acid in dam plasma following a daily gavage dose of vinpocetine in HSD rats from GD6 to GD18.

Table 2 (40 KB)

Table 3. Toxicokinetic parametersa for vinpocetine and apovincaminic acid in fetuses.

Toxicokinetic parametersa for vinpocetine and apovincaminic acid in fetuses following a daily gavage dose of vinpocetine in HSD rats from GD6 to GD18.

Table 3 (25 KB)

Table 4. Toxicokinetic parameters for vinpocetine and apovincaminic acid in amniotic fluid.

Toxicokinetic parameters for vinpocetine and apovincaminic acid in amniotic fluid following a daily gavage dose of vinpocetine in HSD rats from GD6 to GD18.

Table 4 (29 KB)

Table 5. Comparison of dose-normalized AUC and Cmax of vinpocetine and apovincaminic acid in rodents.

Comparison of dose-normalized AUC and Cmax of vinpocetine and apovincaminic acid in rodents.

Table 5 (85 KB)

Table 6. Comparison of exposure between rats and humans.

Table 6 (83 KB)