Busulfan toxicity

Pezzimenti JF, Kim HC, Lindenbaum J. Eiythroleukemia-like syndrome due to busulfan toxicity in polycythemia vera. Cancer 1976 38(6) 2242-6. 

Induced changes in biological parameters of the cell cycle have been assayed in various doses and exposure times, all indicating cytotoxic effects to rapidly proliferating tissues, in particular to the cells of the granulopoietic lineage of the bone marrow. In all studies busulfan toxicities occur in an AUC-dependent manner inducing apoptosis. In vitro studies show decrease in proliferation and colony formation and arrest of cell cycle in G2 phase. The development of apoptosis occurred secondarily to the interruption of other vital metabolic pathways that still remain to be characterized. Typical chemotherapeutic-induced apoptotic effects are observed in in vitro studies. 

A patient with acute myeloid leukaemia started treatment with a 4-day course of busulfan 1 mg/kg four times daily followed by cyclophosphamide for 2 days before bone marrow transplantation. At the time he was also receiving ketobemidone 1 g daily for a rectal fissure. Busulfan plasma levels after the first dose were elevated (AUC increased by about one-third). Later, when the dose of ketobemidone was reduced and morphine substituted, busulfan levels decreased. The authors suggest that ketobemidone should not be used with high-dose busulfan unless monitoring is possible dose adjustments may be required to prevent busulfan toxicity. An alternative analgesic should be considered. 

List the nonhematologic toxicity to high-dose chemotherapy used in myeloablative preparative regimens, specifically busulfan-induced seizures, hemorrhagic cystitis, gastrointestinal toxicities, and sinusoidal obstruction syndrome. 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

At usual therapeutic dosages, busulfan is selectively toxic to granulocyte precursors rather than lymphocytes. Thrombocytopenia and anemia and less commonly, nausea, alopecia, mucositis, and sterility also may occur. Unusual side effects of busulfan include gynecomastia, a general increase in skin pigmentation, and interstitial pulmonary fibrosis. 

Some toxicants are known to affect the female reproductive system and processes. Exposure to the alkylating agents cyclophosphamide and vincristine can lead to loss of female sexual function. Cyclophosphamide may attack and damage the oocytes, cells that lead to egg formation. Pharmaceutical busulfan damages ovaries. The 7,8-diol-9,10-epoxide of benzo(a)pyrene, as well as some other metabolites of polycyclic aromatic hydrocarbons, can be toxic to oocytes. 

CALCIUM CHANNEL BLOCKERS BUSULFAN t plasma concentrations of busulfan and t risk of toxicity of busulfan such as veno-ocdusive disease and pulmonary fibrosis, when co-administered with diltiazem, nifedipine or verapamil Due to inhibition of CYP3A4-mediated metabolism of busulfan by these calcium channel blockers. Busulfan clearance may be l by 25%, and the AUC of busulfan may t by 1500 p,mol/L Monitor clinically for veno-ocdusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC of below 1500 p,mol/L per minute tends to prevent toxicity... 

BUSULFAN MEFRONIDAZOLE t busulfan levels Uncertain Watch for early features of toxicity... 

BUSULFAN TIOGUANINE t risk of nodular regenerative hyperplasia of the liver, oesophageal varices and portal hypertension Mechanism uncertain Monitor liver function and for clinical and biochemical indices of liver toxicity (e.g. ascites, splenomegaly). Ask patients to report any symptoms suggestive of oesophageal bleeding... 

BUSULFAN H2 RECEPTOR BLOCKERS -CIMETIDINE t adverse effects of alkylating agent, e.g. myelosuppression Additive toxicity Monitor more closely monitor FBC regularly... 

CIMETIDINE BUSULFAN, CARMUSTINE, CHLORAMBUCIL CYCLOPHOSPHAMIDE, ESTRAMUSTINE, IFOS-FAMIDE, LOMUSTINE, THIOTEPA, TREOSULFAN T adverse effects of cytotoxic, e.g. myelosuppression Additive toxicity. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9 Monitor more closely monitor FBC regularly. Avoid co-administration of cimetidine with cyclophosphamide... 

Slattery JT, Sanders JE, Buckner RL, Schaffer RL, Lambert KW, Langer FP, Anasetti C, Bensinger WI, Fisher LD, Appelbaum FR, Hansen JA. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 1995 16 31-42. 

In 24 patients with graft-versus-host disease, metronidazole significantly increased busulfan plasma concentrations from 452 to 807 ng/ml (41). The authors concluded that metronidazole should not be administered simultaneously with busulfan, because of the risk of severe toxicity and/or mortality. 

Openshaw H, Lund BT, Kashyap A, Atkinson R, Sniecinski I, Weiner LP, Forman S. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning report of toxicity and immunological monitoring. Biol Blood Marrow Transplant 2000 6(5A) 563-75. 

Reduced elimination and increased toxicity of busulfan co-administered with itraconazole has been postulated (67). 

Schallier D, Impens N, Warson F, Van Belle S, De Wasch G. Additive pulmonary toxicity with melphalan and busulfan therapy. Chest 1983 84(4) 492-3. 

Exposure to this compound therapeutically is by the oral route. Since variation in the AUG for oral busulfan results in substantial risk of over- or undertreatment with risk of toxicity or relapse, the use of an intravenous (IV) formulation has been studied. IV formulation reduces this variability by eliminating variability in absorption. Busulfan is a small, highly lipophilic molecule that easily passes the blood-brain barrier. The typical dosage level (tablet form) is 4-8 mg daily. The recommended intravenous dose given prior to bone marrow transplant is 0.8mgkg body weight given as a 2 h infusion every 6 h for 4 days. 

Busulfan is a bifunctional alkylating agent. It consists of two methanesulfonate groups attached at opposite ends of a four-carbon alkyl chain. Alkylating agents form covalent DNA interstrand cross-links that inhibit DNA synthesis. Toxicity of busulfan s alkylation of intercellular nucleophiles is associated with its... 

Busulfan is a potent cytotoxic drug. Early in development of the compound, in vivo experiments indicated that busulfan caused severe depression in the bone marrow. The most prevalent acute toxic effects associated with busulfan in animals are severe pancytopenia from bone marrow failure. Associated in vivo experiments show bone marrow aplasia, stromal cell damage, immunosuppression (impaired T-lymph-ocyte function), and pronounced adverse effects on reproductive glands, germ cells, and fertility in animals (lowest effective dose tested was 2 mg kg... 

The difficulty in determining dose delivered with oral administration of high-dose busulfan in preparative regimens for hematopoietic stem cell transplantation results in lethal toxicity due to overdosing and increased potential for relapse with recurrent disease. Oral pharmacokinetic studies ineffectively determine proper AUC for reliable establishment for a proper therapeutic dose. Studies with IV formulations have demonstrated that all patients are evaluable. With the development of a limited sampling strategy to analyze proper AUC over intermittent time periods, improved patient risk profiles for busulfan have been implemented in clinical practice. 

Busulfan has been shown to induce gene mutations and chromosomal damage in bacteria, fungi, plant species. Drosophila, and in animal cell lines in culture. Busulfan does not require S9 activation in in vitro toxicity assays. 

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