Description: <p><b>Orlistat</b> (tetrahydrolipstatin; anti-obesity drug; OTC 60 mg, Rx 120 mg). A potent, minimally absorbed <b>gastrointestinal lipase inhibitor</b> that reduces dietary fat absorption (~30% at 120 mg TID).</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) Irreversible inhibition of gastric + pancreatic lipases (↓ triglyceride hydrolysis)<br>
2) ↓ Chylomicron formation → ↓ systemic lipid flux<br>
3) Secondary metabolic shifts (weight loss–mediated insulin sensitivity changes)</p>
<p><b>Bioavailability / PK relevance:</b> Very low systemic absorption (<1%); primary action is intraluminal in gut. Most systemic mechanistic cancer data derive from higher in-vitro concentrations or off-target effects (e.g., FASN inhibition).</p>
<p><b>In-vitro vs oral exposure:</b> Many anti-cancer studies use concentrations likely exceeding achievable plasma levels from standard dosing (qualifier: high concentration only for direct tumor cytotoxicity).</p>
<p><b>Clinical evidence status:</b> Approved for obesity; cancer evidence largely preclinical/observational; no robust oncology RCT indication.</p>
<b>Inhibits</b> lipase and is used to facilitate weight loss.<br>
<br>
<h3>Orlistat — Cancer vs Normal Cell Pathway Map</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Fatty Acid Synthase (FASN)</td>
<td>↓ (high concentration only)</td>
<td>↔ (low FASN dependence)</td>
<td>R/G</td>
<td>Lipid synthesis blockade; apoptosis</td>
<td>Well-known off-target in vitro; many tumors overexpress FASN. Clinical relevance limited by low systemic exposure.</td>
</tr>
<tr>
<td>2</td>
<td>Lipid availability / metabolic flux</td>
<td>↓ (indirect)</td>
<td>↓ (systemic)</td>
<td>G</td>
<td>Reduced lipid supply</td>
<td>Weight-loss–mediated effect; may indirectly reduce pro-tumor metabolic signaling (insulin/IGF axis).</td>
</tr>
<tr>
<td>3</td>
<td>PI3K/AKT/mTOR</td>
<td>↓ (model-dependent)</td>
<td>↔ / ↓ (metabolic improvement)</td>
<td>R/G</td>
<td>Reduced anabolic signaling</td>
<td>Often secondary to lipid stress or metabolic shifts; not primary gut mechanism.</td>
</tr>
<tr>
<td>4</td>
<td>Apoptosis (caspase activation)</td>
<td>↑ (high concentration only)</td>
<td>↔</td>
<td>R/G</td>
<td>Programmed cell death</td>
<td>Observed in cancer lines at supra-physiologic levels; translation uncertain.</td>
</tr>
<tr>
<td>5</td>
<td>ROS / lipid peroxidation stress</td>
<td>↑ (lipid stress–related; model-dependent)</td>
<td>↔</td>
<td>P/R</td>
<td>Metabolic oxidative stress</td>
<td>Linked to FASN inhibition; not central to approved mechanism.</td>
</tr>
<tr>
<td>6</td>
<td>NRF2 axis</td>
<td>↔ (insufficient evidence)</td>
<td>↔</td>
<td>R/G</td>
<td>Not a dominant axis</td>
<td>No consistent evidence of primary NRF2 modulation at therapeutic exposure.</td>
</tr>
<tr>
<td>7</td>
<td>Ferroptosis (lipid metabolism link)</td>
<td>↑ (theoretical / model-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Lipid vulnerability shift</td>
<td>FASN inhibition could alter lipid composition; ferroptosis relevance remains investigational.</td>
</tr>
<tr>
<td>8</td>
<td>HIF-1α / Warburg coupling</td>
<td>↓ (indirect; metabolic improvement)</td>
<td>↔</td>
<td>G</td>
<td>Reduced pro-growth metabolic signaling</td>
<td>Likely secondary to weight loss and insulin reduction rather than direct tumor action.</td>
</tr>
<tr>
<td>9</td>
<td>Ca²⁺ signaling</td>
<td>↔</td>
<td>↔</td>
<td>P/R</td>
<td>No primary role</td>
<td>Not a recognized mechanistic axis for orlistat.</td>
</tr>
<tr>
<td>10</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>Minimal systemic exposure</td>
<td>Low absorption limits direct anti-tumor applicability; GI side effects and fat-soluble vitamin malabsorption noted.</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min; R: 30 min–3 hr; G: >3 hr</p>