Paclitaxel concentration

Apoptosis is another important mechanism for cell poisoning, in addition to tubulin assembly promotion and microtubule stabilization for paclitaxel, especially at a high concentration (sub pM to pM level). It is also observed that in higher concentrations (5 to 50 pM), paclitaxel induced tumor necrosis through microtubules rather than apoptosis. " " Note that paclitaxel concentration in the clinic is lower than pM. 

Other data suggest that neutropenia may be related to pharmacological exposure, and phase 1 studies have shown that the severity of paclitaxel-induced neutropenia correlates with the area under the paclitaxel concentration-time curve (36). 

Desai, N. et al.. Increased antitnmor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, alhnmin-honnd paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin. Cancer Res., 12(4), 1317, 2006. 

Figure 19.14. Concentration of fluorescent paclitaxel to PC-3 cells. Note increased paclitaxel concentration to cells.

Hyaluronidase is the antidote of choice for vinca alkaloid and high-concentration epipodophyllotoxin extravasations. Hyaluronidase breaks down hyaluronic acid, which functions as tissue cement. This promotes absorption of the extravasated drug away from the local site. Hyaluronidase also may be used for paclitaxel extravasations, but there are conflicting reports regarding its efficacy.39 Hyaluronidase should not be used with anthracycline extravasations because enhancement of local spread may occur. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

The amount of dequalinium in DQAsomes was measured using fluorescence spectroscopy (ex. 335 nm, em. 360 nm). At these wavelengths, paclitaxel does not display any fluorescence and therefore does not interfere with the determination of dequalinium. For measurements, 3 pL DQAsomes were dissolved in 3mL methanol, resulting in a concentration of dequalinium, which lies within the linear range of a previously determined standard curve. 

The literature is also starting to show a significant volume of papers that concentrate on the possible mechanisms of paclitaxel resistance seen in tumors (15). These include ... 

In most studies where a supraadditive interaction was seen, cells were incubated with the drug prior to irradiation (38). In general the use of moderate concentrations (5-100 nmol/L) of paclitaxel in the culture medium for over 24 h lead to maximum sensitization. Most studies used actively proliferating cells in order to conduct their experiments and most investigators reached the conclusion that maximal radiosensitization occurred when cells were arrested in G2 and M, as this part of the cell cycle is the most sensitive to radiation damage. This assumption does, however, presuppose that the majority of the G2/M arrested cells will not die unless they are exposed to ionizing XRT. Plateau phase, i.e., nonproliferating, cells were found to be sensitized to radiation... 

Jordan MA, Wendell K, GardinerS, Derry WB, CoppH, Wilson L. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res 1996 56(4) 816-825. 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

The crude paclitaxel is dissolved in dichloromethane, filtered, and solvent-exchanged into a mixture of dimethylformamide (DMF) and formamide. This solution is loaded onto a chromatography column and eluted with acetonitrile/ water as the mobile phase. The acceptably pure fractions are combined and concentrated to remove acetonitrile, and the paclitaxel is extracted into dichloromethane. Finally, the dichloromethane is replaced with IPA (distillative exchange) and paclitaxel API is isolated by crystallization. 

MALDI-IMS has been employed extensively to investigate the distribution of either commercially available or prospective drugs in tissues. Troendle et al. (1999) reported using MALDI in conjunction with a quadrupole ion trap equipped with a laser microprobe to detect the dmg paclitaxel [molecular weight (MW) 853] from rat liver and human ovarian tumor tissue. The liver tissue was incubated with a solution of paclitaxel, while the ovarian tumor tissue was from an animal dosed with paclitaxel in vivo. The concentration of drug was approximately 50mg/kg in each tissue of interest. In both cases, no localization of the dmg was observed. 

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