Efficient brain uptake of piperine and its pharmacokinetics characterization after oral administration

Abstract

1. Piperine, the major biological active component in black pepper has been associated with miscellaneous pharmacological effects, especially on central nervous system. To correlate with its neurological activity, a comprehensive pharmacokinetic profile of piperine in brain, plasma and cerebrospinal fluid after oral administration in rats was investigated in this study. 2. It was noted that piperine could efficiently penetrate and homogeneously distribute into brain with similar pharmacokinetics profiles in each region. In addition, piperine concentrations in brain and plasma were found to be comparable with brain to plasma area under curve extrapolated to infinity (AUC) ratios of 0.95 and 1.10 for total concentration and unbound concentrations, respectively. Piperine also demonstrated high affinity toward brain tissue (98.4-98.5%) and plasma protein (96.2-97.8%) leading to a brain distribution volume of 36.32 ± 1.40 ml/g brain. Moreover, its efficient membrane permeability (P values of 5.41 ± 0.40 × 10 cm/s and 4.78 ± 0.16 × 10 cm/s for basolateral to apical and apical to basolateral transport in Caco-2 monolayer model) and limited hepatic metabolism (Cl of 8.15 μl/min/mg) could also contribute to its quick and high extent brain exposure. 3. In summary, this study for the first time demonstrated high brain penetration potency of piperine could be resulted from its high brain tissue affinity and membrane permeability together with its limited liver metabolism.

Dietary Piperine is Transferred into the Milk of Nursing Mothers

“…[36] BBB permeability predictions for piperine and analogs from in vitro models and experimental permeability data from animal studies have shown that piperine diffuses into the brain after oral administration. [37,38] Given the evidence that both caffeine and piperine cross the BBB and are detectable in human milk after oral ingestion suggests that compounds that cross the BBB could be found in human milk and vice versa. Interestingly, the phenomenon of increased bioavailability of curcumin when piperine was co-administered did not lead to an abundance of curcumin in human milk.…”

Safety Aspects of the Use of Isolated Piperine Ingested as a Bolus

“…Information on piperine serum or plasma levels observed in rats after oral administration is not uniform. With oral doses of 3.5, 20, 35 or 250 mg piperine/kg bw, corresponding plasma C max values of approximately 0.45, 3.4, 5.4-6.0 or 12.7 µmol piperine/L were observed in different studies [37,[41][42][43]. However, other studies observed higher C max values with approximately 9.9 µmol/L after an oral dose of 20 mg piperine/kg bw [44] or levels of approximately 28-39 µmol/L after a dose of 170 mg piperine/kg bw [34,36].…”

“…However, other studies observed higher C max values with approximately 9.9 µmol/L after an oral dose of 20 mg piperine/kg bw [ 44 ] or levels of approximately 28–39 µmol/L after a dose of 170 mg piperine/kg bw [ 34 , 36 ]. Plasma protein binding was about 98% in rats receiving an oral dose of 35 mg piperine/kg bw [ 42 ]. Furthermore, piperine was shown to efficiently penetrate and homogeneously distribute into the brain of rats after oral piperine doses (35 mg/kg bw), leading to comparable AUC (0-∞) -values in brain and plasma with a brain–plasma AUC ratio of 0.95.…”

“…Furthermore, piperine was shown to efficiently penetrate and homogeneously distribute into the brain of rats after oral piperine doses (35 mg/kg bw), leading to comparable AUC (0-∞) -values in brain and plasma with a brain–plasma AUC ratio of 0.95. However, based on the AUC (0-∞) values, the piperine level in cerebrospinal fluid was around 50 times lower than in brain or plasma [ 42 ].…”

Downregulation of Candidate Gene Expression and Neuroprotection by Piperine in Streptozotocin-Induced Hyperglycemia and Memory Impairment in Rats

“…Group A: Vehicle control (VC) Group B: Diabetic control (STZ) Group C: Piperine treatment (STZ/PIP) Group D: Sitagliptin group (STZ/SITA) Both piperine (20 mg/kg/day) and Sitagliptin (25 mg/kg/day) were administered daily for 4 weeks during the course of the experiment. The dose of 20 mg/kg/day of piperine is considered the standard dose, also mentioned in the literature (Ren et al, 2018;Guo et al, 2020).…”