Paclitaxel

853.90600

853.91

608-826-9

358882

2811

DTXSID9023413

White to off-white crystalline powder|Needles from aqueous methanol

2932999021

221.29000

4.12660

Taxol appears as needles (from aqueous methanol) or fine white powder. An anti-cancer drug.

1.39g/cm3

213-216 °C (decomp)

957.115ºC at 760 mmHg

532.644ºC

-49 ° (C=1, MeOH)

methanol: 50 mg/mL, clear, colorless

2-8ºC

LD50 intraperitoneal in mouse: 128mg/kg

Specific optical rotation: -49 deg at 20 °C/D (methanol); UV max absorption 2 (methanol): 227, 273, nm (E= 29,800,1700)

278.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Clear colorless to slightly yellow viscous solution /Paclitxel Injection USP/

May be sensitive to prolonged exposure to moisture. (NTP, 1992).

Alcohols and Polyols

III

6.1(b)

UN 1544

3

R40; R41

S22; S26; S36/37/39; S45

DA8340700

Xn

Stable. Incompatible with strong oxidizing agents. Combustible.

P261-P280-P284-P304 + P340-P305 + P351 + P338 + P310-P342 + P311

H315-H317-H318-H334-H335-H341-H361

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/|For more Disposal Methods (Complete) data for TAXOL (8 total), please visit the HSDB record page.

Chem & Eng News 70 (41): 30-2 (1992); A discussion concerning the development and synthesis of taxol, a new antitumor drug.|Van Ingen G et al; Sudden Unexpected Death Due to Taxus Poisoning: A report of five cases, with review of the literature. Forensic Sci Int 56 (1): 81-7 (1992). The clinical and autopsy findings are summarized, the diagnostic aspects are discussed and the literature concerning Taxus is reviewed.|Correia JJ; Effects of Antimitotic Agents on Tubulin Nucleotide Interactions. Pharmacol Ther 52 (2): 127-47 (1991). The interaction of antimitotic drugs with guanine nucleotides in the tubulin-microtubule system is reviewed. Taxol stoichiometrically induces microtubule formation and, in the presence of guanosine triphosphate, assembly associated guanosine triphosphate hydrolysis.

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H315 (86.34%): Causes skin irritation [Warning Skin corrosion/irritation]|P201, P202, P260, P261, P264, P270, P271, P272, P273, P280, P281, P285, P302+P352, P304+P340, P304+P341, P305+P351+P338, P308+P313, P310, P312, P314, P321, P332+P313, P333+P313, P342+P311, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 227 companies from 25 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this material can be controlled with a dry chemical, carbon dioxide, or Halon extinguisher. (NTP, 1992)

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: As an immediate precautionary measure, isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids. SPILL: Increase, in the downwind direction, as necessary, the isolation distance shown above. FIRE: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2016)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this material from moisture, and store it in a freezer. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/|/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/|For more Preventive Measures (Complete) data for TAXOL (20 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/

Paclitaxel has been associated with serum aminotransferase elevations in 7% to 26% of patients, but values greater than 5 times the upper limit of normal (ULN) in only 2% of those receiving the highest doses. Similar rates of alkaline phosphatase elevations and occasional mild bilirubin elevations also occur. The abnormalities are usually asymptomatic, mild and self-limited, rarely requiring dose modification or discontinuation. Paclitaxel has not been linked convincingly to instances of delayed, idiosyncratic clinically apparent liver injury with jaundice. However, the hypersensitivity reactions that occur with infusions of paclitaxel can be severe and accompanied by acute hepatic necrosis. The liver injury may be relatively mild and anicteric (Case 1), but can also be severe with rapid onset of multiorgan failure and death. At least one instance of acute liver failure following a hypersensitivity reaction to paclitaxel has been published in the literature and recent modifications of the product labels for paclitaxel and docetaxel mention the occurrence of toxic deaths following severe infusion reactions. Because paclitaxel is often given with other antineoplastic agents, liver injury arising during therapy cannot always be reliably attributed to paclitaxel rather than to other specific agents. Furthermore, paclitaxel in combination with other anticancer agents may be associated with reactivation of hepatitis B, increased risk of opportunistic viral infections, sinusoidal obstruction syndrome or sepsis, any of which can cause liver test abnormalities or clinically apparent liver injury.

Concomitant administration of CNS depressants such as antihistamines or opiates with paclitaxel should be undertaken with caution as these drugs may cause potentiation of CNS depression caused by the alcohol contained in the paclitaxel formulation.|Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/sq m and cisplatin doses of 50 or 75 mg/sq m resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/sq m induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/sq m to 75 mg/sq m), the mean neutrophil count nadir was 98/uL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. ...|... Pharmacokinetic studies show that administration of cisplatin followed by conventional paclitaxel decreases paclitaxel clearance by approximately 25-33%. When cisplatin and paclitaxel must be administered sequentially, the sequence of paclitaxel followed by cisplatin is recommended. Increased severity of neutropenia and thrombocytopenia have been reported when paclitaxel is administered (by 24-hour IV infusion) followed by cyclophosphamide.|Administration of paclitaxel followed by carboplatin was associated with similar rates of neutropenia but less severe thrombocytopenia compared with carboplatin alone; a pharmacodynamic mechanism for the interaction between the drugs has been postulated since the pharmacokinetics of the agents were unchanged.|For more Interactions (Complete) data for TAXOL (8 total), please visit the HSDB record page.

Taxol is a component found in the bark of the Pacific Yew tree, Taxus brevifolia.

While data specific to taxol were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ ... exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/

Paclitaxel is an antineoplastic agent which acts by inhibitor of cellular mitosis and which currently plays a central role in the therapy of ovarian, breast, and lung cancer. Therapy with paclitaxel has been associated with a low rate of serum enzyme elevations, but has not been clearly linked to cases of clinically apparent acute liver injury.

Antineoplastic Agents

Antineoplastic Agents, Phytogenic; Radiation-Sensitizing Agents|Standard formulation paclitaxel requires the use of solvents, such as Cremphor-EL, which contribute to some of the toxicities commonly associated with paclitaxel-based therapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel. The formulation is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin into a nanoparticle colloidal suspension. The human albumin-stabilized paclitaxel particles have an average size of 130 nm. Nab-paclitaxel has several practical advantages over Cremphor-EL-paclitaxel, including a shorter infusion time (30 min) and no need for premedications for hypersensitivity reactions. The nab-paclitaxel formulation eliminates the impact of Cremphor-EL on paclitaxel pharmacokinetics and utilizes the endogenous albumin transport mechanisms to concentrate nab-paclitaxel within the tumor. A recent Phase III trial compared nab- and Cremphor-EL-paclitaxel in patients with metastatic breast cancer. Patients treated with nab-paclitaxel experienced a higher response, longer time to tumor progression and, in patients receiving second-line or greater therapy, a longer median survival. Patients treated with nab-paclitaxel had a significantly lower rate of severe neutropenia and a higher rate of sensory neuropathy. The preclinical and clinical data indicate that the nab-paclitaxel formulation has significant advantages over Cremphor-EL-paclitaxel.|As first line and subsequent therapy for the treatment of advanced carcinoma of the ovary. As first-line therapy, paclitaxel is indicated in combination with cisplatin.|Adjuvant treatment of node-positive breast cancer administration sequentially to standard doxorubicin-containing combination chemotherapy. In the clinical trial, there was an overall favorable effect on disease-free and overall survival in the total population of patients with receptor-positive and receptor-negative tumors, but the benefit has been specifically demonstrated by available data (mean follow-up, 30 months) only in the patients with estrogen and progesterone receptor-negative tumors. Indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Previous therapy should have included an anthracycline unless clinically contraindicated.|For more Therapeutic Uses (Complete) data for TAXOL (9 total), please visit the HSDB record page.

Administer paclitaxel under the supervision of a health care provider experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilitates are readily available.|Do not give paclitaxel therapy to patients with solid tumors who have baseline neutrophil counts of less than 1,500 cells/cu mm, and do not give to patients with AIDS-related Kaposi sarcoma if the baseline neutrophil count is less than 1,000 cells/cu mm. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, perform frequent peripheral blood cell counts on all patients receiving paclitaxel.|Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite premedication. Pretreat all patients with corticosteroids, diphenhydramine, and H2 antagonists. Do not rechallenge patients who experience severe hypersensitivity reactions to paclitaxel with the drug.|An albumin form of paclitaxel may substantially affect a drug's functional properties relative to those of drug in solution. Do not substitute for or with other paclitaxel formulations. /Paclitaxel (albumin-bound)/|For more Drug Warnings (Complete) data for TAXOL (62 total), please visit the HSDB record page.

Paclitaxel bound to nanoparticles of the serum protein albumin is delivered via endothelial transport mediated by albumin receptors, and the resulting concentration of paclitaxel in tumor cells is increased compared with that achieved using an equivalent dose of conventional paclitaxel. Like conventional paclitaxel, albumin-bound paclitaxel has a large volume of distribution. Following 30-minute or 3-hour IV infusion of 80-375 mg/sq m albumin-bound paclitaxel, the volume of distribution averaged 632 L/sq m. The volume of distribution of albumin-bound paclitaxel 260 mg/sq m by 30-minute IV infusion was 53% larger than the volume of distribution of conventional paclitaxel 175 mg/sq m by 3-hour IV infusion. /Paclitaxel (albumin-bound)/|Following IV administration, paclitaxel is widely distributed into body fluids and tissues. Paclitaxel has a large volume of distribution that appears to be affected by dose and duration of infusion. Following administration of paclitaxel doses of 135 or 175 mg/sq m by IV infusion over 24 hours in patients with advanced ovarian cancer, the mean apparent volume of distribution at steady state ranged from 227-688 L/sq m. The steady-state volume of distribution ranged from 18.9-260 L/sq m in children with solid tumors or refractory leukemia receiving paclitaxel 200-500 mg/sq m by 24-hour IV infusion. Paclitaxel does not appear to readily penetrate the CNS, but paclitaxel has been detected in ascitic fluid following IV infusion of the drug. It is not known whether paclitaxel is distributed into human milk, but in lactating rats given radiolabeled paclitaxel, concentrations of radioactivity in milk were higher than those in plasma and declined in parallel with plasma concentrations of the drug.|For the dose range 80-375 mg/sq m, increase in dose of albumin-bound paclitaxel was associated with a proportional increase in AUC.354 The duration of infusion did not affect the pharmacokinetic disposition of albumin-bound paclitaxel. Following 30-minute or 3-hour IV infusion of albumin-bound paclitaxel 260 mg/sq m, the peak plasma concentration averaged 18,741 ng/mL. /Paclitaxel (albumin-bound)/|Peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) following IV administration of paclitaxel exhibit marked interindividual variation. Plasma concentrations of paclitaxel increase during continuous IV administration of the drug and decline immediately following completion of the infusion. Following 24-hour IV infusion of paclitaxel at doses of 135 or 175 mg/sq m in patients with advanced ovarian cancer, peak plasma concentrations averaged 195 or 365 ng/mL, respectively; the increase in dose (30%) was associated with a disproportionately greater increase in peak plasma concentration (87%), but the increase in AUC was proportional. When paclitaxel was administered by continuous IV infusion over 3 hours at doses of 135 or 175 mg/sq m in patients with advanced ovarian cancer, peak plasma concentrations averaged 2.17 or 3.65 ug/mL, respectively; the increase in dose (30%) was associated with disproportionately greater increases in peak plasma concentration (68%) and AUC (89%).|For more Absorption, Distribution and Excretion (Complete) data for TAXOL (8 total), please visit the HSDB record page.

Paclitaxel is extensively metabolized in the liver. Metabolism of paclitaxel to its major metabolite, 6alpha-hydroxypaclitaxel, is mediated by cytochrome P-450 isoenzyme CYP2C8,1 185 187 202 354 while metabolism to 2 of its minor metabolites, 3'-p-hydroxypaclitaxel and 6alpha,3'-p-dihydroxypaclitaxel, is catalyzed by CYP3A4.|The elimination of nonradioactive taxol in bile and urine was investigated in the rat after administration via the caudal vein (10 mg/kg). As in humans, no metabolites of taxol were detected by HPLC in rat urine, and only 10% of the injected taxol was recovered in urine over a 24 hr period. In contrast, 11.5% and 29% of the injected taxol was recovered in rat bile as unchanged taxol and metabolites, respectively. Among the nine taxol metabolites detected by HPLC, the side chain at C13, which is required for pharmacological activity, had been removed in only one minor metabolite, baccatin III. The chemical structures of the two major hydroxylated metabolites were determined by MS (fast atom bombardment and desorption chemical ionization) and (1)H NMR spectroscopy. One was a taxol derivative hydroxylated on the phenyl group at C3 of the side chain at C13, while the other corresponded to a taxol derivative hydroxylated in the m-position on the benzoate of the side chain at C2. Although these two major taxol metabolites were as active as taxol in preventing cold microtubule disassembly, they were, respectively, 9 and 39 times less cytotoxic as taxol on in vitro L1210 leukemia growth. These results show for the first time that there is a significant hepatic metabolism of taxol.|To investigate how taxane's substituents at C3' affect its metabolism, ... the metabolism of cephalomannine and paclitaxel, a pair of analogs that differ slightly at the C3' position /was compared/. After cephalomannine was incubated with human liver microsomes in an NADPH-generating system, two monohydroxylated metabolites (M1 and M2) were detected by liquid chromatography/tandem mass spectrometry. C4'' (M1) and C6alpha (M2) were proposed as the possible hydroxylation sites, and the structure of M1 was confirmed by (1)H NMR. Chemical inhibition studies and assays with recombinant human cytochromes P450 (P450s) indicated that 4''-hydroxycephalomannine was generated predominantly by CYP3A4 and 6alpha-hydroxycephalomannine by CYP2C8. The overall biotransformation rate between paclitaxel and cephalomannine differed slightly (184 vs. 145 pmol/min/mg), but the average ratio of metabolites hydroxylated at the C13 side chain to C6alpha for paclitaxel and cephalomannine varied significantly (15:85 vs. 64:36) in five human liver samples. Compared with paclitaxel, the major hydroxylation site transferred from C6alpha to C4'', and the main metabolizing P450 changed from CYP2C8 to CYP3A4 for cephalomannine. In the incubation system with rat or minipig liver microsomes, only 4''-hydroxycephalomannine was detected, and its formation was inhibited by CYP3A inhibitors. Molecular docking by AutoDock suggested that cephalomannine adopted an orientation in favor of 4''-hydroxylation, whereas paclitaxel adopted an orientation favoring 3'-p-hydroxylation. Kinetic studies showed that CYP3A4 catalyzed cephalomannine more efficiently than paclitaxel due to an increased V(m). Our results demonstrate that relatively minor modification of taxane at C3' has major consequence on the metabolism.

5.3-17.4 hours after 1 and 6 hour infusions at dosing levels of 15-275 mg/sq m|Following IV infusion of paclitaxel over periods ranging from 6-24 hours in adults with malignancy, plasma concentrations of paclitaxel appeared to decline in a biphasic manner in some studies, with an average distribution half-life of 0.34 hours and an average elimination half-life of 5.8 hours. However, additional studies, particularly those in which paclitaxel is administered over shorter periods of infusion, show that the drug exhibits nonlinear pharmacokinetic behavior. In patients receiving paclitaxel 175 mg/sq m administered by 3-hour IV infusion, the distribution half-life averages 0.27 hours and the elimination half-life averages 2.33 hours.|Following 30-minute or 3-hour IV infusion of 80-375 mg/sq m albumin-bound paclitaxel, ... terminal half-life albumin-bound paclitaxel was about 27 hours. ... /Paclitaxel (albumin-bound)/

Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis. In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G2 phase, the phase of the cell cycle in which cells are most radiosensitive.|Paclitaxel is an antimicrotubule antineoplastic agent. Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell. By binding in a reversible, concentration-dependent manner to the beta-subunit of tubulin at the N-terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules. Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, the presence of antimitotic drugs). While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication.|... Taxol induces tubulin polymerization and forms extremely stable and nonfunctional microtubules. Taxol has demonstrated broad activity in preclinical screening studies, and antineoplastic activity has been observed in several classically refractory tumors. These tumors include cisplatin resistant ovarian carcinoma in phase II trials and malignant melanoma and non-small cell lung carcinoma in phase I studies.

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: TOXIC; inhalation, ingestion or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. (ERG, 2016)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. /Antineoplastic agents/|Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. /Antineoplastic agents/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antineoplastic agents/|Enhanced elimination. Because of the rapid intracellular incorporation of most of these agents, dialysis and other extracorporeal removal procedures are generally not effective. /Antineoplastic agents/

/SIGNS AND SYMPTOMS/ Overdosage of conventional paclitaxel in pediatric patients may be associated with acute ethanol toxicity because of the presence of dehydrated alcohol in the formulation.|/SIGNS AND SYMPTOMS/ Signs and symptoms of acute overdose: Ventricular arrhythmias, erythema, congestive heart failure, dyspnea, neuropathy (peripheral), myopathy, dysphagia, diplopia, chest pain, stomatitis, wheezing, neuritis, leukopenia; neutropenia; agranulocytosis; granulocytopenia.|/SIGNS AND SYMPTOMS/ Limited information is available on acute overdosage of paclitaxel. Overdosage with paclitaxel would be expected to produce effects such as myelosuppression, peripheral or sensory neurotoxicity, and mucositis.|/CASE REPORTS/ A 58-years-old woman with a metastatic ovarian carcinoma who had chest pain, nausea and collapse during their first Taxol infusion /is described/. The infusion was stopped and the patient was submitted to the intensive care unit (ICU) to exclude an acute coronary syndrome. The electrocardiography (ECG) showed a third-degree heart block and ST elevation in II, III and avF. In the initial and in the control laboratory investigation values of cardiac enzymes (creatinine kinase and Troponine T) remained normal. The control ECG after 30 minutes turned back to normal. After one day the patient was submitted back to a normal ward. ...|For more Human Toxicity Excerpts (Complete) data for TAXOL (11 total), please visit the HSDB record page.

Parenteral: For injection, concentrate, for IV infusion: 6 mg/mL Onxol (with dehydrated alcohol 49.7% (v/v) and polyoxyl 35 castor oil 527 mg/mL) (Teva), Paclitaxel Injection (with dehydrated alcohol 49.7% (v/v) and polyoxyl 35 castor oil 527 mg/mL) (Bedford, Mayne, UDL), Taxol (with dehydrated alcohol 49.7% (v/v) and polyoxyl 35 castor oil 527 mg/mL) (Bristol-Myers Squibb).|Parenteral: For injectable suspension, for IV infusion: 100 mg (of paclitaxel) Abraxane (Abraxis). /Paclitaxel (albumin-bound)/|Paclitaxel is commercially available as protein-bound particles consisting of paclitaxel bound to albumin; the mean particle size of albumin-bound paclitaxel is about 130 nm. Albumin-bound paclitaxel is a sterile, white to yellow lyophilized powder that must be reconstituted for use as an injectable suspension; there are no solvents. Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin.|Because paclitaxel is extremely hydrophobic, the commercially available injection concentrate is a sterile, nonaqueous solution of the drug in polyoxyl 35 castor oil (Cremophor EL, polyoxyethylated castor oil) and dehydrated alcohol. Commercially available paclitaxel for injection concentrate is a clear, colorless to slightly yellow, viscous solution. Following dilution of paclitaxel for injection concentrate with 5% dextrose and 0.9% sodium chloride injection or 5% dextrose and Ringer's injection, solutions containing 0.6 or 1.2 mg of paclitaxel per mL maintain a pH of 4.4-5.6 for up to 27 hours.

Because of the limited number of plants available, 4 million Taxus trees have been planted to allow for continued supply of this drug.|Antimicrotubule agent extracted from the Pacific yew tree ... being investigated for the use in treatment of lymphoma and mammary carcinoma in veterinary medicine

Analyte: paclitaxel; matrix: pharmaceutical preparation (injection solution); procedure: micellar electrokinetic capillary chromatography with ultraviolet detection at 230 nm|Analyte: paclitaxel; matrix: pharmaceutical preparation (bulk, injection solution); procedure: reversed-phase high-performance liquid chromatography with ultraviolet detection at 230 nm; limit of detection: 310-370 ng/mL|Analyte: paclitaxel; matrix: pharmaceutical preparation (injection solution); procedure: high-performance liquid chromatography with ultraviolet detection at 227 nm|Analyte: paclitaxel; matrix: pharmaceutical preparation (injection solution); procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm|For more Analytic Laboratory Methods (Complete) data for TAXOL (11 total), please visit the HSDB record page.

Analyte: paclitaxel; matrix: blood (plasma), urine; procedure: micellar electrokinetic chromatography with ultraviolet detection at 230 nm; limit of detection: 20 ng/mL (plasma), 50 ng/mL (urine)|Analyte: paclitaxel; matrix: blood (plasma); procedure: high-performance liquid chromatography with ultraviolet detection at 227 nm; limit of detection: 10 ng/mL|Analyte: paclitaxel; matrix: blood (plasma); procedure: reversed-phase high-performance liquid chromatography with ultraviolet detection at 227 nm; limit of detection: 0.15 nM|For more Clinical Laboratory Methods (Complete) data for TAXOL (11 total), please visit the HSDB record page.