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Rapamycin's bioavailability (in raw or simple solid form) is extremely low, typically ~1–2% oral bioavailability in humans.

This poor absorption is due to:

• Poor aqueous solubility: Rapamycin is lipophilic and practically insoluble in water, limiting dissolution in the GI tract.
• High molecular weight (~914 Da): Too large for passive diffusion through intestinal lining.
• First-pass hepatic metabolism: Rapidly metabolized by CYP3A4 enzymes in the liver and intestines.
• P-glycoprotein efflux substrate: Pumped back into the gut lumen by intestinal P-gp, reducing net absorption.

Why SMEDDS or Microemulsions Are Needed:

Without these, absorption is negligible, and the therapeutic effect would be unreliable or absent. This is why Rapamune (SMEDDS-based) was developed to raise it to a usable ~14% and allow oral administration in transplant patients and off-label longevity research.

🧠 Rapamycin Bioavailability: Route Comparison
Route	Approx. Bioavailability	Advantages	Challenges	Formulation Strategies
Oral (raw/standard)	~1–2%	Convenient	Poor solubility, extensive 1st-pass metabolism, P-gp efflux	None (base compound only)
Oral (SMEDDS / Rapamune)	~14%	Convenient, approved, reproducible	Still undergoes some 1st-pass metabolism	Microemulsion: solubilization, lymphatic absorption
Oral (Nanoformulations)	~10–20% (varies)	Potential for higher uptake	Stability, scale-up	Liposomes, solid lipid nanoparticles, nanocrystals
Sublingual / Buccal	~10–30% (theoretical)	Bypasses liver first-pass metabolism	Low water solubility, bitter taste, mucosal irritation	Ethanol-based sprays, cyclodextrin complexes, mucoadhesive gels
Transdermal (Topical)	<1% (unformulated) / ~5–10% (enhanced)	Bypasses GI/liver, localized delivery	Poor skin penetration (large molecule)	Ethosomes, transfersomes, nanoemulsions
Intranasal	~10–20% (theoretical)	Rapid absorption, avoids 1st-pass	Irritation, mucociliary clearance	Nanoemulsions, cyclodextrin-inclusion complexes
Rectal	~5–15% (est.)	Partial 1st-pass avoidance	Patient acceptability, formulation variability	Suppositories, lipid-based enemas
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