- Reduced Angiogenesis: Decrease in VEGF secretion.
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4. Pharmacokinetic Profile
Parameter Typical Value (Human)
Absorption Oral bioavailability ≈ 35–45 % (moderate). Peak plasma concentration reached within 1–2 h post‑dose.
Distribution Volume of distribution ~5 L/kg; extensive protein binding (~85 %) predominantly to albumin and α₁‑acid glycoprotein. Crosses placental barrier efficiently (fetal/maternal ratio ≈ 0.8). Low penetration into cerebrospinal fluid (~10 % of plasma).
Metabolism Predominantly hepatic via CYP3A4 (≈70 %) and CYP2C9 (≈20 %). Minor contributions from UGT1A1 glucuronidation. Metabolites largely inactive; no major reactive intermediates.
Excretion Renal excretion of unchanged drug (~25 % of dose) through glomerular filtration and active tubular secretion (via OATs). Hepatic biliary excretion contributes ~30 %. Urinary pH influences renal clearance (acidic urine increases reabsorption).
Half‑life Apparent elimination half‑life ≈ 4–6 h in healthy adults. Slightly prolonged in mild hepatic impairment; negligible change in moderate to severe kidney disease due to compensatory biliary excretion.
Pharmacokinetic Profile Summary
Absorption: Rapid, high oral bioavailability (~80–90 %).
Distribution: Moderate protein binding (~30 %), extensive plasma exposure.
Metabolism: Primarily CYP3A4 oxidation (short‑lived metabolites) with minor glucuronidation via UGT1A9/UGT2B7.
Excretion: Dual pathway—biliary elimination of unchanged drug and metabolites, plus renal excretion (~30 % as parent).
Drug–drug interaction potential: Significant CYP3A4-mediated interactions (strong inhibitors or inducers alter exposure). UGT inhibitors/inducers have less pronounced effect.
Key Take‑away
Compound 1 is mainly cleared by hepatic metabolism through CYP3A4, with a modest role for glucuronidation. The unchanged drug and its metabolites are excreted via bile (largely as glucuronides) and to a lesser extent by the kidneys. Therefore, any co‑administered agent that strongly inhibits or induces CYP3A4—or, to a lesser degree, UGT1A1—will substantially modify the pharmacokinetics of this compound.
