Rapamycin PEARL Clinical Trial Unblinding

[cl-user]

@DrFraser

AI correctly details this effect - here is a copy/paste

Yes, AI is pretty cool indeed. I explicitly asked that question to the very latest ChatGPT o1, which supposedly “thinks” and auto-validate its replies, and here is its reply which I find pretty clear. The key here is “The inhibitory compounds in grapefruit juice have limited systemic absorption and thus have a negligible effect on hepatic CYP3A4 activity.”

@ChatGPT o1

grapefruit juice impacts sirolimus pharmacokinetics by increasing its absorption and plasma concentrations, but it does not significantly affect the elimination half-life of sirolimus.

Explanation:

1. Sirolimus Pharmacokinetics:
• Metabolism and Elimination:
• Sirolimus, also known as rapamycin, is an immunosuppressive agent used primarily to prevent organ transplant rejection.
• It is extensively metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme system in both the small intestine and liver.
• The drug has a relatively long elimination half-life of approximately 62 hours (range: 46–78 hours).

• Absorption:
• Sirolimus has a low oral bioavailability (~14%) due to significant first-pass metabolism by intestinal CYP3A4 and efflux by P-glycoprotein (P-gp) in the gut wall.

2. Grapefruit Juice Interaction:
• Inhibition of Intestinal CYP3A4:
• Grapefruit juice contains compounds called furanocoumarins (e.g., bergamottin, 6’,7’-dihydroxybergamottin) that are potent inhibitors of intestinal CYP3A4.
• Effect on Sirolimus:
• Reduced First-Pass Metabolism: Inhibition of intestinal CYP3A4 leads to decreased metabolism of sirolimus in the gut wall.
• Increased Absorption: More of the drug enters the systemic circulation, resulting in higher peak plasma concentrations (Cmax) and increased area under the curve (AUC).
• Inhibition of P-glycoprotein:
• Grapefruit juice may also inhibit P-glycoprotein, further enhancing sirolimus absorption.

3. Impact on Sirolimus Half-Life:
• Absorption vs. Elimination:
• Primary Effect on Absorption: The main impact of grapefruit juice is on the absorption phase, increasing the amount of sirolimus that reaches systemic circulation.
• Minimal Effect on Hepatic CYP3A4:
• The inhibitory compounds in grapefruit juice have limited systemic absorption and thus have a negligible effect on hepatic CYP3A4 activity.
• Elimination Processes Unchanged: Since the liver’s ability to metabolize sirolimus remains largely unaffected, the elimination half-life of the drug does not significantly change.

• No Significant Change in Half-Life:
• While plasma concentrations rise, the duration the drug stays in the body (half-life) remains relatively constant.