The eukaryotic cell cycle is regulated by cyclin-dependent kinases (CDKs). CDK4 and CDK6, which are activated by D-type cyclins during the G 1 phase of the cell cycle, are thought to be responsible for phosphorylation of the retinoblastoma gene product (pRb). The tumor suppressor p16INK4A inhibits phosphorylation of pRb by CDK4 and CDK6 and can thereby block cell cycle progression at the G 1 /S boundary. Phosphorylation of the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II by general transcription factor TFIIH is believed to be an important regulatory event in transcription. TFIIH contains a CDK7 kinase subunit and phosphorylates the CTD. We have previously shown that p16INK4A inhibits phosphorylation of the CTD by TFIIH. Here we report that the ability of p16INK4A to inhibit CDK7-CTD kinase contributes to the capacity to induce cell cycle arrest. These results suggest that p16INK4A may regulate cell cycle progression by inhibiting not only CDK4-pRb kinase activity but also by modulating CDK7-CTD kinase activity. Regulation of CDK7-CTD kinase activity by p16INK4A thus may represent an alternative pathway for controlling cell cycle progression.Cyclin-dependent kinases (CDKs) regulate cell cycle progression (references 13, 21, and 28) and references therein). CDK4 and CDK6 are activated by D-type cyclins and participate in controlling the G 1 -to-S phase transition by phosphorylating the retinoblastoma gene product (pRb). Phosphorylation of pRb induces remodeling of transcriptional repressor complexes at pRb-regulated genes and causes the release of transcription factors such as E2F. Free E2F can then activate the transcription of genes required for entering S phase (36,41). p16 INK4A is a tumor suppressor gene product which binds CDK4 and inhibits CDK4-mediated phosphorylation of pRb (27). Overexpression of p16INK4A can block cell cycle progression through the G 1 -to-S phase boundary in a pRB-dependent manner (16,19). Many p16 INK4A mutants identified from human tumors have been shown to have defects in this activity (15,16,19,20,22,31). These data suggest that the CDK4-inhibitory activity of p16 INK4A is involved in regulating cell cycle progression through the G 1 /S boundary.Koh et al. have described an interesting phenotype associated with a p16INK4A mutant, G101W, that was originally identified in a familial melanoma kindred (14, 16). The G101W mutant was defective in inhibiting CDK4, although overexpression of the G101W mutant in an osteosarcoma cell line provoked cell cycle arrest at G 1 . In this mutant, the CDK4-pRb kinase-inhibitory activity of p16 INK4A apparently does not correlate with the ability to induce cell cycle arrest in G 1 when overexpressed. These results raise the possibility that an additional biochemical activity of p16INK4A might contribute to the ability to arrest cell cycle progression. (15,16,19,20,22,31,38,39). These data suggest that the ability to inhibit pRb kinase activity may not be the sole determinant of the tumor suppressor activity of p16 INK4A ....

The objectives of this study were to characterize the concentration‐time profiles of total radioactivity equivalent and unchanged cefiderocol, the route(s) of elimination and mass balance, and safety of cefiderocol after intravenous administration of a single 1000‐mg (100 μCi) dose of [ 14 C]‐cefiderocol as a 1‐hour infusion in healthy adult male subjects. Unchanged cefiderocol accounted for the majority of total radioactivity in plasma, and the partitioning of total radioactivity into red blood cells was negligible. The recovery of total radioactivity was complete in all subjects within 120 hours after initiation of the infusion (101.5% of the administered dose). Cefiderocol‐related material was primarily excreted into urine, with 98.7% of the administered dose of [ 14 C]‐cefiderocol excreted as total radioactivity into urine and negligible excretion into feces. Based on the results of metabolite profiling, cefiderocol accounted for 92.3% of area under the concentration‐time curve of total radioactivity in plasma and accounted for 90.6% of the administered dose excreted into urine. Metabolism was a minor route of elimination for cefiderocol. Cefiderocol was generally safe and well tolerated in healthy adult male subjects. In conclusion, unchanged cefiderocol represents the majority of total radioactivity in plasma. Cefiderocol is primarily excreted as unchanged drug into urine. This study indicates that cefiderocol and drug‐related material did not remain in the body.

Cefiderocol has no clinically significant DDI potential via drug transporters.

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