Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma.
Temsirolimus is metabolized by hydrolysis to sirolimus, the principal active metabolite. Both temsirolimus and sirolimus also are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.
The in vitro metabolism of temsirolimus, (rapamycin-42-[2,2-bis-(hydroxymethyl)]-propionate), an antineoplastic agent, was studied using human liver microsomes as well as recombinant human cytochrome P450s, namely CYP3A4, 1A2, 2A6, 2C8, 2C9, 2C19, and 2E1. Fifteen metabolites were detected by liquid chromatography (LC)-tandem mass spectrometry (MS/MS or MS/MS/MS). CYP3A4 was identified as the main enzyme responsible for the metabolism of the compound. Incubation of temsirolimus with recombinant CYP3A4 produced most of the metabolites detected from incubation with human liver microsomes, which was used for large-scale preparation of the metabolites. By silica gel chromatography followed by semipreparative reverse-phase high-performance liquid chromatography, individual metabolites were separated and purified for structural elucidation and bioactivity studies. The minor metabolites (peaks 1-7) were identified as hydroxylated or desmethylated macrolide ring-opened temsirolimus derivatives by both positive and negative mass spectrometry (MS) and MS/MS spectroscopic methods. Because these compounds were unstable and only present in trace amounts, no further investigations were conducted. Six major metabolites were identified as 36-hydroxyl temsirolimus (M8), 35-hydroxyl temsirolimus (M9), 11-hydroxyl temsirolimus with an opened hemiketal ring (M10 and M11), N- oxide temsirolimus (M12), and 32-O-desmethyl temsirolimus (M13) using combined LC-MS, MS/MS, MS/MS/MS, and NMR techniques. Compared with the parent compound, these metabolites showed dramatically decreased activity against LNCaP cellular proliferation.
◉ Summary of Use during Lactation:Temsirolimus is a prodrug of sirolimus. Because no information is available on the use of temsirolimus or sirolimus during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. The manufacturer recommends that breastfeeding be discontinued during temsirolimus therapy and for 3 weeks following the last dose.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of the principal active metabolite sirolimus). Concomitant use with a potent CYP3A4 inhibitors should be avoided; if no alternative is available, consideration should be given to temsirolimus dosage adjustment.
CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of the principal active metabolite sirolimus). Concomitant use with potent CYP3A4 inducers should be avoided; if no alternative is available, consideration should be given to temsirolimus dosage adjustment.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
在同时使用血管紧张素转换酶（ACE）抑制剂治疗期间观察到的血管性水肿型反应。建议谨慎使用。
Angioedema-type reactions observed during concomitant therapy with angiotensin-converting enzyme (ACE) inhibitors. Caution is advised.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
接受联合治疗的病人颅内出血风险增加。需谨慎。
Increased risk of intracerebral bleeding in patients receiving concomitant therapy. Caution is advised.
Following administration of a single 25 mg dose of temsirolimus in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of variation, CV =14%), and mean AUC in blood was 1627 ng.hr/mL (CV=26%). Typically Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.
Following a single 25 mg intravenous dose, mean steady-state volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements.
Following IV administration of a single radiolabeled dose of temsirolimus, approximately 78% of the total radioactivity is recovered in feces and 4.6% in urine within 14 days.
