Distribution
Irinotecan is a hydrophilic compound with a large volume of distribution (400 L/m2). At physiological pH, irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) are present in two pH-dependent equilibrium isoforms; the anti tumor active lactone ring which hydrolyzed to the carboxylate isoform.In plasma, the majority of irinotecan and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells.Irinotecan has a linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for irinotecan and a two-compartmental model for SN-38.SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after infusion. Also SN-38 exhibit a second peak in the plasma concentration because of its enterohepatic re-circulation and its release from erythrocytes. Metabolism
Activation by carboxylesterases and butyrylcholinesteras
About 2–5% of the pro-drug irinotecan is hydrolyzed into its active metabolite SN-38 in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE). CES2 has a 12.5-fold higher affinity for irinotecan than CES1. While, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES. After conversion, SN-38 is actively transported to the liver by the organic anion transporting polypeptide (OATP) 1B1 transporter. Inactivation by uridine diphosphate glucuronosyltransferases
SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extra-hepatic (UGT1A1, UGT1A7, UGT1A10) and excreted into the bile. Several UGT polymorphisms affects irinotecan pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity.
And when a patient with LHON or toxic/nutritional optic neuropathy has a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used, due to increased risk of optic nerve ischemia in response to this anti-hypertensive.Idebenone  has been shown in a small placebo-controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset. α-Tocotrienol-quinone, a vitamin E metabolite, has had some success in small open-label trials in reversing early onset vision loss.Various treatment approaches have had early trials or been proposed, but so far none with convincing evidence of usefulness or safety for treatment or prevention, including brimonidine, minocycline,   curcumin, glutathione, near infrared light treatment, and viral vector techniques. "Three person in vitro fertilization" is a proof-of-concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established. Idebenone
Idebenone is a short-chain benzoquinone that interacts with the mitochondrial electron transport chain to enhance cellular respiration. When used in people with LHON, it is believed to allow electrons to bypass the dysfunctional complex I. Successful treatment with idebenone was initially reported in a small number of patients.Two large-scale studies have demonstrated the benefits of idebenone. The Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) evaluated the effects of idebenone in 85 patients with LHON who had lost vision within the prior five years.