## 4 Poor PK Profiles but Safe for Humans
As shown in Table 2, the IC\({}_{50}\) values of delpazolid and linezolid at which mitochondrial protein synthesis in the two human cell-lines (K562 and AC16) were similar at 3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\) indicated that these agents killed approximately 50% of human cells at 3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\). Thus, 3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\) of delpazolid and linezolid is the mitochondrial damage limit. At higher concentrations, mitochondrial protein synthesis is affected severely, leading to cell death. Therefore, considering 3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\) as the reference value at which toxicity of the two drugs occurs, a phase 1 trial based on linezolid 600 mg BID revealed that the linezolid plasma concentration was maintained at above the IC\({}_{50}\) (3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) for 12 h. However, delpazolid 800 mg maintained the IC\({}_{50}\) above the mitochondrial damage limit for only 3 h, after which it was cleared rapidly from the blood. Therefore, delpazolid provides ample time for mitochondria to recover its protein synthesis function. In addition, increasing the delpazolid dose to 1200 mg raises the IC\({}_{50}\) \begin{table}
\begin{tabular}{l l l l l} \hline
**Compound** & **Bacteria** & **Human Mitochondria (IC\({}_{50}\))** & **Animal Mitochondria [14]** \\ \hline \multirow{4}{*}{Delpazolid} & _Escherichia coli_ & K562 cell & AC16 cell & Rat, Rabbit (liver \& heart) \\  & 2.6 \(\mathrm{\SIUnitSymbolMicro g/mL}\) & 4.8 \(\mathrm{\SIUnitSymbolMicro g/mL}\) & 10.9 \(\mathrm{\SIUnitSymbolMicro g/mL}\) & NA \\  & (0.8 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) & (1.5 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) & (3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) & \\ \cline{1-1} \cline{2-5} \multirow{2}{*}{Linezolid} & 11.6 \(\mathrm{\SIUnitSymbolMicro g/mL}\) & 3.1 \(\mathrm{\SIUnitSymbolMicro g/mL}\) & 10.0 \(\mathrm{\SIUnitSymbolMicro g/mL}\) & \\  & (3.9 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) & (1.0 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) & (3.4 \(\mathrm{\SIUnitSymbolMicro g/mL}\)) & 12.8 \(\mathrm{\SIUnitSymbolMicro g/mL}\) \\ \hline \end{tabular}
\end{table} 
Table 2: Antibiotic properties of oxazolidinones on bacterial and mitochondrial protein synthesis. Figure 2: Mean plasma concentrations of linezolid and delpazolid in adults following oral dosing (mean \(\pm\) standard deviation, \(n=6\)). to above 3.4 \(\mu\)g/mL for only 5 h, after which it also clears from the blood. Therefore, the low AUC with rapid clearance in delpazolid ironically minimizes cellular toxicity. Consequently, repeated BID dosing of delpazolid results in much lower levels of myelosuppression because of the lower mitochondrial protein synthesis inhibition compared to linezolid [9; 10]. Therefore, the side effects of delpazolid were much milder than those of linezolid. The difference in side effects despite the similar structure of the two drugs may be due to differences in their chemical structures. The cyclic amidrazone side chain of delpazolid facilitates more rapid clearance and prevents accumulation in the plasma compared to linezolid. Thus, rapid clearance has been demonstrated as a key advantage that reduces myelosuppression compared to linezolid. Therefore, delpazolid may replace linezolid for MDR-TB for long-term treatment [11].