https://pubmed.ncbi.nlm.nih.gov/26036652/
https://www.tandfonline.com/doi/full/10.3109/10717544.2015.1039667
Piperine increased the bioavailability of rapamycin by 4.8-fold, outperforming even grapefruit juice at 3.5-fold. What’s your ideas? Should I buy black pepper extract dietary supplements?
A user here tested this a year ago: Does piperine increase rapamycin absorption? - #4 by EverVital
Some regular black pepper should work.
FWIW…
The paper is from September 2016.
No other paper on this?
I only found this.
A summary and evaluation of the paper. This is specially engineered biodegradable polymeric nanoparticles, so not too relevant to us I would think. Great for drug designers…
Rapamycin is among the most potent inhibitors of aging pathways and tumor proliferation, yet its clinical efficacy is crippled by poor water solubility and active expulsion by intestinal P-glycoprotein efflux pumps. In this study, researchers engineered biodegradable polymeric nanoparticles that co-encapsulate rapamycin with piperine, the bio-enhancing alkaloid found in black pepper. By pairing piperine-mediated efflux inhibition with sustained-release polymer engineering, the dual-drug formulation achieved a 365 percent increase in oral drug bioavailability in rats and cut the concentration required to kill resistant breast cancer cells in half.
Rapamycin holds a preeminent place in geroscience and oncology due to its targeted inhibition of mechanistic target of rapamycin (mTOR), a master regulator of cellular growth, translation, and metabolic decline. However, translating oral rapamycin into consistent clinical outcomes faces a steep pharmacokinetic barrier. The drug exhibits extremely poor aqueous solubility (2.6 micrograms per milliliter) and is recognized as a substrate by P-glycoprotein (P-gp), an ATP-dependent efflux pump situated along the gut lining and on tumor cell membranes that expels therapeutic molecules back into the intestinal lumen or extracellular space. Consequently, oral dosing yields low and variable systemic absorption.
To solve this clearance bottleneck, a team of pharmaceutical scientists developed a dual-action nanocarrier using poly(D,L-lactide-co-glycolide) (PLGA), an FDA-approved, biodegradable polymer. The core breakthrough lies in co-encapsulating rapamycin with piperine, a naturally occurring alkaloid from black pepper known to inhibit P-gp efflux and downregulate Phase I drug-metabolizing enzymes.
The resulting nanoparticles, measuring roughly 134 nanometers in diameter, shield both payloads and provide a biphasic release profile. The formulation delivers an initial pulse of piperine to suppress mucosal efflux transporters, followed by zero-order, sustained diffusion of rapamycin lasting over seven weeks.
In physiological barrier testing using everted rat intestinal sacs, the dual-loaded nanoparticles increased rapamycin permeation across the gut barrier from undetectable baseline levels to nearly 5 percent. When tested in female Sprague-Dawley rats at a dose of 10 milligrams per kilogram, the co-loaded nanoparticles prolonged peak plasma concentrations from 24 to 72 hours and achieved a 4.65-fold increase in total systemic drug exposure (area under the curve) compared to conventional rapamycin suspensions.
In cell culture experiments using aggressive MDA-MB-231 triple-negative breast cancer cells, the nanoparticle formulation lowered the half-maximal inhibitory concentration (IC50) from 20.35 micromolar for free rapamycin to 11.39 micromolar. By combining mechanical nanocarrier protection with biochemical transporter inhibition, the researchers demonstrated a viable platform to dramatically enhance the oral delivery and cellular toxicity of poorly bioavailable longevity and anticancer compounds.
Actionable Insights For individuals exploring longevity therapeutics, this study offers critical takeaways regarding oral rapamycin bioavailability:
Bio-enhancement Dynamics: Co-administering rapamycin with piperine or encapsulating it in targeted lipid/polymer matrices substantially enhances systemic absorption. In animal models, adding piperine in standard suspension increased total systemic drug absorption by 70.3 percent (1.70-fold), while nanoparticle co-delivery increased it by 364.9 percent (4.65-fold).
Potency at Lower Doses: Nanoparticle delivery reduced the rapamycin concentration required for 50 percent cancer cell suppression by 44.0 percent (an absolute decrease of 8.96 micromolar, representing a 1.79-fold potency gain). This indicates that bioavailability enhancers could allow lower oral doses to achieve comparable therapeutic tissue levels.
Pharmacokinetic Caution: Nanoparticle delivery extended the time to maximum blood concentration from 24 hours to 72 hours, with sustained circulation exceeding 7 days. For longevity applications, where intermittent dosing is typically preferred to avoid chronic mTOR complex 2 (mTORC2) inhibition, sustained-release formulations carry a risk of persistent immunosuppression and metabolic dysregulation unless dosing intervals are substantially lengthened.
Context/Source