Doxorubicin metabolism

Xanthine dehydrogenase (EC 1.1.1.204), the enzymatic precursor of xanthine oxidase (EC 1.1.3.22) reacts with doxorubicin via a two-electron reduction (Yee and Pritsos 1997). This reduction is different from the modified and more extensively studied form xanthine oxidase, which reacts with doxorubicin via a one-electron reduction. Under hypoxic conditions, the formation of large quantities of 7-deoxydoxorubicin aglycone, a deactivation product of doxorubicin metabolism, may serve to moderate the antineoplastic activity of doxorubicin. Under aerobic conditions, however, xanthine dehydrogenase activation led to a greater rate of formation of oxygen radicals than xanthine oxidase thereby possibty potentiating the cytotoxicity of doxorubicin to aerobic tumour cells. 

ABVD Doxorubicin Anthracycline Hepatic metabolism Cardiomyopathy... 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

Transfection ofmouse SlPphosphatase into HEK 293 cells, resulting in a 3-fold increase in membrane SIP phosphatase activity, caused a 50% deaease in SIP levels (reduced by 0.6 pmol/nmol phospholipid) and a 2 fold inaease in ceramide (inaeased by 23 pmol/nmol phospholipid) whereas sphingosine levels were similar to vector controls (0.8 pnnol/nmol phosphohpid). SIP phosphatase transfected cells underwent apoptosis in response to serum withdrawal, C2-ceramide, peroxide or doxorubicin with 2-3 fold higher frequency compared to vector-transfected control cells. Surprisingly, exogenously added SIP, which normally confers protechon, inaeased apoptosis. This may be due to its metabolism to ceramide (Mandala et al, 2000) although other factors may also be involved. 

The anthracyclines, apart from valrubicin, are administered intravenously. Doxorubicin is rapidly distributed to tissues and slowly eliminated in faeces and urine with an elimination half-life of several days. Daunorubicin undergoes extensive metabolism in the liver, among others to the active daunorubi-cinol, and is eliminated as inactive products with an elimination half-live of approximately 30 hours. Epimbicin and idambicin have similar kinetic profiles as daunombicin with respectively epirubici-nol and idarubicinol as their major metabolic products. The kinetic behavior of mitoxantrone resembles more that of doxorubicin with a very slow elimination from the body mainly as parent compound or as inactive metabolites. The anthracyclines do not cross the blood-brain barrier. 

Doxorubicin is not absorbed orally, and because of its ability to cause tissue necrosis must not be injected intramuscularly or subcutaneously. Distribution studies indicate rapid uptake in all tissues except the CNS. Extensive tissue binding, primarily intranuclear, accounts for the prolonged elimination half-life. The drug is extensively metabolized in the liver to hydroxylated and conjugated metabolites and to aglycones that are primarily excreted in the bile. 

Idarubicin (Idamycin) differs from its parent compound, daunorubicin, by the absence of the methoxy group in the anthracycline ring structure. Its mechanisms of action and resistance are similar to those of doxorubicin and daunorubicin however, it is more lipophilic and more potent than these other anthracy-clines. Idarubicin undergoes extensive hepatic metabolism and biliary excretion. Adverse reactions of idarubicin are similar to those of its congeners. 

The pharmacokinetics fCD and HlftCD after intravenous administration have been assessed (Frijlinket al., 1990). As determined at doses of 25,100, and 200 mg/kg in permanently cannulated rats, plasma levels of both CDs decreased rapidly upon injection. Within 24 h after administration, most of the doses were excreted unchanged via urine. There was no evidence forsigniLcant metabolism of the intravenously administered CDs. The pharmacokinetics and the tissue concentrations of methyl-p-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination were studied (Grosse et al., 1999). Results indicated that DOX did not modify MEBCD pharmacokinetic proLle, but MEBCD reduced signiLcantly the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX. 

Uchegbu, I.F., et al. 1995. Distribution, metabolism and tumoricidal activity of doxorubicin administered in sorbitan monostearate (span-60) niosomes in the mouse. Pharm Res 12 1019. 

When the heart can no longer pump an adequate supply of blood to meet the metabolic needs of the tissues or in relation to venous return, cardiac failure may ensue. The causes of cardiac failure are complex, but stem from mechanical abnormalities (e.g., pericardial tamponade), myocardial failure (e.g., cardiomyopathy and inflammation), and arrhythmias. In high-output failure, the cardiac output, which may be normal or even higher than normal, is not sufficient to meet the metabolic requirement of the body. Cardiac failure may predispose a patient to congestive heart failure, which is a state of circulatory congestion. Toxic injury, caused by agents such as doxorubicin, the alkaloid emetine in ipecac syrup, cocaine, or ethyl alcohol, is another way by which the functional integrity of the heart may also be compromised. 

Cyclosporin A readily inhibits CYP3A metabolism and may lead to significant pharmacokinetic interactions (288). Several studies have been performed using cyclosporin A as a P-gp modulator in combination with etoposide, doxorubicin, and paclitaxel as described below. 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-5], interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabolites, interfering with complex metabolic pathways in the cell, include methotrexate [59-05-2], 5-fluorouracil [51-21-8], and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxorubicin [23214-92-8] have been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

DOXORUBICIN AZATHIOPRINE t risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis. Additive myelotoxic effects. Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppres-sion, immunosuppression and hepatotoxicity Avoid co-administration... 

DOXORUBICIN ANTIEPILEPTICS -BARBITURATES i doxorubicin levels Induction of hepatic metabolism Monitor for 1 efficacy of doxorubicin... 

IMATINIB DOXORUBICIN t risk of myelosuppression due to t plasma concentrations Due to 1 metabolism of doxorubicin by CYP3A4 isoenzymes owing to inhibition of those enzymes Monitor for t myelosuppression, peripheral neuropathy, myalgias and fatigue... 

CANNABIS CYTOTOXICS -CYCLOPHOSPHAMIDE, DOXORUBICIN, IFOSFAMIDE, LOMUSTINE, VINCA ALKALOIDS Unpredictable changes in plasma concentration. Risk of toxicity or therapeutic failure, particularly of drugs with a narrow therapeutic index Induction or inhibition of CYP3A4-mediated metabolism by cannabis. It is not yet known whether the effects are dependent on the degree of cannabis consumption Be aware. Watch for signs of toxicity, especially when cannabis use abruptly changes... 

Camaggi CM, Comparsi R, Strocchi E, Testoni F, Angelelli B, Pannuti F. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study. Cancer Chemother Pharmacol 1988 21(3) 221-8. 

Nony P, GuastaUa JP, Rebattu P, Landais P, Lievre M, Bontemps L, Itti R, Beaune J, Andre-Fouet X, Janier M. In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy. Cancer Chemother Pharmacol 2000 45(5) 375-80. 

Liposomal doxorubicin in Myocet has systemic avail-abihty, metabolism, and excretion similar to that of conventional doxorubicin, but at a slower rate (8). In dogs, the plasma concentrations of doxorubicin from Myocet were 1000-fold greater than conventional doxorubicin at 6 hours, but the difference diminished at 24 hours (9). This distinguishes Myocet from DoxU, which persists in the circulation for significantly longer. 

Paclitaxel is metabolized by the cytochrome P450 isoenzymes CYP2C and CYP3A4 (53), and drugs that inhibit or induce these isozymes would be expected to alter the metabolism of paclitaxel. In vitro ranitidine, diphenhydramine, vincristine, vinblastine, and doxorubicin had little or no effect on the metabolism of paclitaxel, but... 

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