Administration<unk>  can be administrated by 30- or 90-minute intravenous infusions of either 125 mg/m2 weekly for four of every six weeks or 350 mg/m2 every three weeks. Distribution<unk>  is a hydrophilic compound with a large volume of distribution (400 L/m2). At physiological pH,<unk>  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<unk>  and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood,<unk>  and SN-38 are bound to platelets and red blood cells.<unk>  has a linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for<unk>  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<unk>  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<unk>  than CES1. While, butyrylcholinesterase has a 6-fold higher activity for<unk>  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<unk>  pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity. Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation is another risk factor for increased toxicity De-conjugation by β-glucuronidases The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38. Metabolism by cytochrome P450 enzymes<unk>  is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10-4-N-(5-aminopentanoic acid)-1-piperidino carbonyloxycamptothecin) and NPC (7-ethyl-10-4-amino-1-piperidino carbonyloxycamptothecin). NPC can be further converted by CES1 and CES2 in the liver to SN-38. Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with<unk> . Transport to bile<unk>  is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2. Elimination<unk>  clearance is mainly biliary (66%) and estimated 12–21 L/h/m2. All metabolites, except SN-38G, are mainly excreted in feces.<unk>  elimination half-lives were reported between 5 to18 h. SN-38 half-lives were reported between 6 to 32 h. There is high (30%) interindividual variability in<unk>  pharmacokinetic parameters which can be altered by several factors including age, sex, dose, administration timing, hepatic function, enzyme activity or hematocrit levels.
Irinotecan
Ifosfamide
Vincristine
Topotecan
Etoposide
Normustine
Trifluridine
Doxorubicin