Tedizolid is administered as a phosphate prodrug that is converted to tedizolid (the circulating active moiety). Prior to excretion, the majority of tedizolid is converted to an inactive sulphate conjugate in the liver, though this is unlikely to involve the action of cytochrome P450-family enzymes.
Therapy with tedizolid has been associated with mild and transient elevations in serum aminotransferase and alkaline phosphatase levels in 1% to 4% of patients, although similar rates of elevations occur in patients with infections treated with comparable agents including linezolid. In all instances, the elevations occurred without symptoms or jaundice and resolved with discontinuation of the drug.
While tedizolid has not been linked to cases of clinically apparent liver disease with jaundice, linezolid, a similar oxazolidinone antibiotic, has been linked to cases of lactic acidosis and systemic injury. This syndrome generally arises after 1 to 8 weeks of therapy and is sometimes associated with evidence of liver injury and jaundice. Lactic acidosis is usually due to dysfunction or loss of hepatic mitochondria, with resulting microvesicular steatosis and disturbed hepatic function (not necessarily accompanied by jaundice or even ALT or alkaline phosphatase elevations). Other serious side effects associated with mitochondrial damage include peripheral and optic neuropathy, pancreatitis, serotonin syndrome and renal injury. The mitochondrial injury is believed to be due to the inhibition of mitochondrial ribosomal function that matches the known effect of the oxazolidinones on bacterial ribosomal function. Lactic acidosis occurs after 1 to 8 weeks of treatment and can be severe, although it resolves rapidly with discontinuation. In contrast, the optic and peripheral neuropathy due to this class of antibiotics resolves more slowly and can be permanent. Lactic acidosis can be fatal, and hepatic dysfunction and jaundice have been mentioned in severe cases attributed to linezolid. This syndrome has yet to be clearly linked to tedizolid therapy.
Likelihood score: E* (unproven but suspected cause of liver injury).
◉ Summary of Use during Lactation:No information is available on the use of tedizolid during breastfeeding. Tedizolid is 70 to 90% bound in maternal plasma, so large amounts are not expected to appear in breastmilk. If tedizolid is required by the mother, it is not a reason to discontinue breastfeeding, but because there is no published experience with tedizolid during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ 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.
来源:Drugs and Lactation Database (LactMed)
毒理性
蛋白质结合
大约70到90%的特迪唑立丁与人血浆蛋白结合。
Approximately 70 to 90% of tedizolid is bound to human plasma proteins.
Tedizolid reaches peak plasma concentrations within three hours for oral administration and within one hour following intravenous administration; the absolute oral bioavailability is approximately 91%. Food has no effect on absorption. When given once daily, either orally or intravenously, tedizolid reaches steady-state concentrations in approximately three days. The Cmax for tedizolid after a single dose/at steady-state is 2.0 ± 0.7/2.2 ± 0.6 mcg/mL for oral administration, and 2.3 ± 0.6/3.0 ± 0.7 mcg/mL for intravenous administration, respectively. Similarly, the Tmax has a median (range) of 2.5 (1.0 - 8.0)/3.5 (1.0 - 6.0) hrs for the oral route and 1.1 (0.9 - 1.5)/1.2 (0.9 - 1.5) hrs when given intravenous. The AUC is 23.8 ± 6.8/25.6 ± 8.4 mcg\*hr/mL for oral and 26.6 ± 5.2/29.2 ± 6.2 mcg\*hr/mL for intravenous.
When given as a single oral dose, approximately 82% of tedizolid is excreted via the feces and 18% in urine. The majority is found as the inactive sulphate conjugate, with only 3% recovered unchanged. Over 85% of the elimination occurs within 96 hours.
The volume of distribution for tedizolid following a single intravenous dose of 200 mg is between 67 and 80 L. In a study involving oral administration of 200 mg tedizolid to steady-state, the volume of distribution was 108 ± 21 L, while a single 600 mg oral dose resulted in an apparent volume of distribution of 113.3 ± 19.3 L. Tedizolid has been observed to penetrate the interstitial space of both adipose and skeletal muscle tissue and is also found in the epithelial lining fluid as well as in alveolar macrophages.
Tedizolid has an apparent oral clearance of 6.9 ± 1.7 L/hr for a single dose and 8.4 ± 2.1 L/hr at steady-state. The systemic clearance is 6.4 ± 1.2 L/hr for a single dose and 5.9 ± 1.4 L/hr at steady-state.
Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds
作者：Aijie Cai、Wenhao Yan、Chao Wang、Wei Liu
DOI：10.1002/anie.202111993
日期：2021.12.20
An aryl radical activation strategy has been developed that can engage unactivated alkyliodides in copper-catalyzed Negishi-type cross-coupling reactions. The strategy is based on the largely overlooked yet highly efficient reactivity of aryl radicals to abstract iodine atoms from alkyliodides.
An improved and efficient method for the preparation of torezolid based on Suzuki cross-coupling reaction as the key step was developed on a gram scale in five steps. The total yield was 44% and the optical purity of torezolid by the improved method was above 99%.
