About 70% (33% presystemic and 37% systemic) of an oral dose is metabolized about equally by cytochrome P450 (CYP) 3A4 and non-CYP3A4 isoenzymes to 4 major metabolites. The systemically available telithromycin is eliminated in the feces as unchanged drug (7%), in urine as unchanged drug (13%), and 37% is metabolized in the liver.
Biotransformation: Hepatic; 37% of the dose is metabolized by the liver. Metabolism accounts for approximately 70% of the dose. The main metabolite represented 12.6% of the AUC while three other metabolites quantified represented 3% or less of the AUC of telithromycin.
In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radiolabeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin. It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.
As with other macrolide antibiotics, telithromycin has been associated with a low rate (1% to 2%) of transient serum enzyme elevations during therapy. These elevations, however, are usually transient and resolve even with drug continuation and a similar rate of serum enzyme elevations can occur with comparator agents. More importantly, telithromycin has been linked to severe forms of acute, clinically apparent hepatotoxicity, first reported within a short time of its general approval for use in the United States. The typical latency to onset of liver injury is rapid, some cases presenting within a day or two of initiation of therapy, the average latency being 1 week. The liver injury is often abrupt in onset with fatigue, weakness, jaundice and fever. The pattern of enzyme elevations is typically hepatocellular and serum aminotransferase levels can be quite high (>1000 U/L). Mild and anicteric cases of liver injury attributed to telithromycin have been reported, but some cases are very severe and associated with rapid development of hepatic failure with ascites and hepatic encephalopathy. Eosinophilia and rash can occur, but are not common. Recurrence of injury with reexposure has been described.
来源:LiverTox
毒理性
相互作用
/使用泰利霉素与匹莫齐特/是禁忌的；存在匹莫齐特水平升高的风险。
/Use of telithromycin with pimozide/ is contraindicated; risk of increased pimozide levels.
When telithromycin is administered with benzodiazepine which are metabolized by CYP 3A4 and undergo a high first-pass effect, serum levels of the other benzodiazepines may increase.
May increase midazolam AUC /when used concurrently with telithromycin/; patients should be monitored and dosage adjustments of midazolam should be considered if necessary.
Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 ug/mL at 6 hours, and remained at 14.1 ug/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 ug/mL 48 hours after the last dose.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
分布容积 - 2.9 L/kg 静脉输注后。广泛分布于全身。泰利霉素可分布到大鼠的乳汁中。
Volume of distribution - 2.9 L/kg following an intervenous infusion. Widely distributed throughout the body. Telithromycin is distributed into breast milk of rats.
Rapidly absorbed, absolute bioavailability is 57% in both young and elderly patients. The rate and extent of absorption are unaffected by food. The AUC following a single dose is 8.25 ug h/mL and 12.5 ug h/mL following multiple dosing.
The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.
