Biomedical subjects

N R Bachur

Publications and source records attributed to N R Bachur.

At least 37 records · Page 2Linked to original sources

PubMed1985

Superoxide radical reactions with anthracycline antibiotics.

The reaction of superoxide with daunorubicin or its aglycones in the aprotic solvents dimethyl sulfoxide and dimethylformamide was studied. This interaction generated the blue anthracycline phenolate anion as monitored by u.v.-visible spectrometry and molecular oxygen as determined by a modified Clark-type oxygen electrode. The visible spectrum of the phenolate anion (gamma max 604, 652 nm) was subject to considerable shifts dependent on the size of the cation present. The phenolate anion could be further oxidized by molecular oxygen to generate the C-6, C-11 (B-ring) semiquinone as detected by a weak electron paramagnetic resonance spectrometry signal. These results raise the possibility that similar reactions of superoxide with anthracyclines in vivo may play a role in the antitumor activity and/or the etiology of the toxic side effects of this class of drugs.

Antibiotics, Antineoplastic↗

PubMed1985

Human pharmacokinetics of esorubicin (4'-deoxydoxorubicin).

The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40 mg/m2. All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 +/- 0.57 microM (mean +/- SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 +/- 7.3 hr. The area under the plasma concentration versus time curve was 0.64 +/- 0.31 microM x hr. Total body plasma clearance was 45.5 +/- 26.8 liter/min/m2 and the apparent volume of the central compartment, 41.0 +/- 24.8 L. A single metabolite, 4'-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 +/- 0.017 microM. The area under the plasma versus concentration time curve for 4'-deoxydoxorubicinol was 0.02 +/- 0.014 microM xhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 +/- 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4'-deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.

Antineoplastic Agents↗

PubMed1985

Comparative murine metabolism and disposition of class II anthracycline antibiotics.

The metabolism and tissue distribution of aclacinomycin A (ACL), marcellomycin (MCM), and musettamycin (MST), three new anthracycline antibiotics, were compared after IV administration to mice. In plasma, total MCM- and ACL-derived fluorescence declined according to first-order kinetics, whereas an initial decline followed by a rebound was observed for MST. In plasma, MCM remained the predominant compound. ACL was eliminated more quickly, and was replaced by two metabolites, the reduced glycoside M1, and an aglycone. In the case of MST, two unidentified metabolites were observed in concentrations equivalent to that of the parent drug. The three drugs were distributed widely to organs, but only ACL achieved measurable concentrations in the brain. Initially, high concentrations of all three drugs were present in the lungs, but these decreased quickly to values similar to those present in the liver and kidneys. Intermediate concentrations of the three drugs were measured in heart and skeletal muscle. Splenic concentrations of all three drugs rose progressively, reaching a maximum at 8 h after injection in the case of ACL and MST, and at 24 h after injection in the case of MCM. Concentrations of the metabolites of MCM and MST were low in all organs except liver and kidney, where the aglycones 7-deoxypyrromycinone and bisanhydropyrromycinone were seen. The metabolism of ACL was extensive. Aglycones were dominant in the liver and kidneys, whereas reduced glycosides predominated in the spleen. These observations indicate that the murine pharmacology of these three structurally similar drugs differs markedly.

Aclarubicin↗

PubMed1985

Human pharmacokinetics of marcellomycin.

In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m2. Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40-50 mg/m2, the peak MCM concentration in plasma was 1.67 +/- 0.61 microM; MCM disappeared from plasma in a triexponential fashion and was undetectable by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11 +/- 0.39 microM X h; plasma clearance of MCM was 1.50 +/- 0.88 l/min/m2. Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m2, fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0% +/- 1.6% of the total dose at 40-50 mg/m2, and to 7.0% +/- 2.3% at 27.5 mg/m2. No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients.

Adult↗

PubMed1985

Electron spin resonance of electrochemically generated free radicals from diaziquone and its derivatives.

The one-electron electrochemical reduction of diaziquone (AZQ) and 12 analogs is analyzed using ESR spectroscopy and cyclic voltammetry. The hyperfine coupling constants arising from the interaction of the unpaired electron with the aziridine nitrogen nuclei fall within 1.20 and 2.26 G. Smaller couplings are observed arising from the protons and nitrogens in the carboethoxyamino groups. The in vitro activity of AZQ and its analogs is examined. Methyl groups in the aziridine rings increase the activity of some analogs. In the absence of aziridines, a chloroquinone compound with only carboethoxyamino groups was surprisingly active. This compound has a more positive cathodic peak than diaziquone.

Animals↗

PubMed1985

Electrochemical and electron spin resonance studies of actinomycin D and other phenoxazones.

Electrochemical studies on actinomycin D (1) and two analogs, 2-amino-3-phenoxazone (2) and 1,2,4-trichloro-7-nitrophenoxazone (3) were analyzed by polarography and ESR spectroscopy. The polarograms of the three compounds in acetonitrile all show two reduction waves. ESR experiments confirm that the first reduction wave corresponds to a one-electron transfer process which produces a phenoxazone free radical anion and the second wave corresponds to a subsequent one-electron transfer producing a diamagnetic dianion. Substitution with electron-withdrawing groups such as NO2 (at C-7) and chloro (at C-1, C-2 and C-4)3 facilitated the reduction of the phenoxazone ring system to a free radical (i.e., half-wave potentials; 1, -0.815 V; 2, -0.920 V; 3, -0.135 V). It was found, by computer simulation of the ESR spectra, that the spin density in the electrochemically generated free radicals from 1, 2 and 3 was preferentially located in the benzenoid ring and at the N-10 nitrogen. For radicals obtained from 1 and 2, only a small residual spin density could be detected in the quinoid ring. Since 1 can be metabolized to a free radical in cells, these free radical forms of 1 and its analogs may represent reactive forms of the phenoxazone nucleus.

Anions↗

PubMed1985

Metabolism and disposition of menogaril (NSC 269148) in the rabbit.

We have investigated the metabolism and disposition, in rabbits, of menogaril (7-OMEN), a new anthracycline antibiotic recently introduced into clinical trials. 7-OMEN was administered by rapid i.v. injection at a dosage of 2.5 mg/kg. 7-OMEN and metabolites were assayed by high performance liquid chromatography. Plasma concentrations of 7-OMEN declined in biexponential fashion with a terminal half-life of 2.7 h. The area under the plasma concentration versus time curve was 1.3 microM X h. The systemic clearance of 7-OMEN was 57.6 ml/min/kg. No metabolite of 7-OMEN was detected in plasma. At 8 h after treatment, the cumulative urinary and biliary excretions of 7-OMEN equivalents amounted to 1.3 and 3.4% of the total administered dose, respectively. 7-OMEN was the predominant fluorescent compound in urine, but four metabolites were also seen. In bile, 7-OMEN represented only 9.6% of the cumulative excretion and six metabolites were observed. Among the organs, lungs contained the highest concentrations of parent drug. Substantial concentrations of metabolites were observed in the kidneys, liver, duodenum, and small intestine. Three of the observed metabolites of 7-OMEN have been tentatively identified as N-demethylmenogaril, 7-deoxynogarol, and N-demethyl-7-deoxynogarol.

Animals↗

PubMed1985

Cellular pharmacology in murine and human leukemic cell lines of diaziquone (NSC 182986).

We investigated the in vitro interaction with and antitumor effect on several murine and human leukemic cell lines of diaziquone (AZQ). L1210 cells accumulated AZQ from Roswell Park Memorial Institute Medium 1640 with or without newborn calf serum by a temperature-dependent and sodium azide-resistant process. AZQ inhibited, in a dose-dependent fashion, [3H]thymidine incorporation into L1210 cells, but this inhibition was slow to develop, requiring approximately 6 hr to become apparent. The minimal inhibitory concentration of AZQ for this process was 0.05 to 0.25 nmol/ml. AZQ was a much less effective inhibitor of L1210 cell [3H]uridine and [14C]valine incorporation. In suspension cultures, AZQ inhibited growth of L1210 and HL-60 cells at minimal inhibitory concentrations of 0.5 to 1 nmol/ml. In soft agar cultures, AZQ inhibited HL-60 cell cloning at minimal inhibitory concentrations of 0.1 to 0.3 nmol/ml. AZQ provoked a dose-dependent increase in oxygen consumption when added to intact L1210, HL-60, and K562 cells and was converted to an AZQ anion free radical by these cells. When the aziridine rings of AZQ were opened by acid treatment, the resulting molecule was not accumulated by L1210 cells, did not provoke O2 consumption, did not form free radicals when added to L1210 cells, and was a much less effective inhibitor of [3H]thymidine incorporation by L1210 cells than was AZQ.

Animals↗

PubMed1985

Radical dimer rescue of toxicity and improved therapeutic index of adriamycin in tumor-bearing mice.

The product of adriamycin (ADR) reductive glycosidic cleavage is the pharmacologically inactive 7-deoxyadriamycin aglycone. Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) is a radical dimer which reacts with ADR in vitro to produce this aglycone. We utilized DHM3 to prevent ADR toxicity in mice. CD2F1 male mice were given a single dose of ADR, 25 mg/kg i.p., which was acutely lethal as indicated by a median survival time of 7 days. DHM3 administered as a single i.p. dose of 50 mg/kg 15 or 30 min following ADR provided significant protection with median survival times greater than 9 wk. Mice bearing ascitic L1210 leukemic cells were given ADR, 0, 6.6, 15, or 25 mg/kg i.p. 1 day following inoculation of tumor. DHM3 administered as a single 50 mg/kg i.p. dose 20 min after ADR had no significant effect on ADR efficacy at the lower dose range (% treated versus control = 171 and 285 for 6.6 and 15.0 mg/kg, respectively). Less than 15% of the animals in these treatment groups were long-term survivors. However, following high doses of ADR (25 mg/kg), DHM3 protected mice from ADR lethality and over 70% of animals were long-term survivors. The determination of parent ADR and ADR aglycone content in several tissues indicated that the concentration of ADR was reduced in those animals that received DHM3 15 min after ADR. Correspondingly an increase in ADR aglycone concentration in each tissue resulted from DHM3 treatment. DHM3 represents a novel class of compounds that can ameliorate ADR toxicity and has potential use as a rescue agent.

Animals↗

PubMed1985

Doxorubicin and cisplatin excretion into human milk.

Plasma and milk concentrations of doxorubicin (DOX) and cisplatin were measured after iv administration of these agents to a lactating patient with ovarian cancer. Cisplatin was undetectable in human milk. Milk concentrations of DOX often exceeded those detected in concomitant plasma samples. For DOX, the highest milk:plasma concentration ratio was 4.43:1 and was observed 24 hours after administration of the drug. The area under concentration versus time curve (AUC) for DOX was approximately the same in plasma and milk. Doxorubicinol was the major metabolite of DOX in plasma and in milk. The AUC for doxorubicinol was ten times higher in milk than in plasma. However, the total amount of anthracycline antibiotic delivered in the milk (maximum concentration of active anthracycline antibiotic: 0.24 mg/L) was negligible.

Adult↗

PubMed1984

Continuous extraction of urinary anthracycline antitumor antibiotics with the horizontal flow-through coil planet centrifuge.

Extraction of doxorubicin (adriamycin) and daunorubicin and their metabolites from human urine was attempted utilizing the horizontal flow-through coil planet centrifuge. Partition coefficients of the drugs for various combinations of non-aqueous phases and aqueous salt solutions were determined. Optimal coefficients for adriamycin and daunorubicin were achieved with n-butanol-0.3 M disodium hydrogen phosphate. Extraction efficiencies of the drugs from human urine comparable to those obtained by standard resin column techniques could be realized by employing the n-butanol-urine (containing 0.3 M disodium hydrogen phosphate) system in the coil planet centrifuge, at flow-rates of 500-600 ml/h, and at 650 rpm revolutional speed. Small quantities of drugs and metabolites could be continuously concentrated into small volumes of the n-butanol phase from large volumes of salted urine. The versatility of the technique was demonstrated by its application to extraction of aclacinomycin A, a novel anthracycline antitumor agent, and its metabolites from human urine.

1-Butanol↗

PubMed1984

Synergistic inhibition of human leukemia cell growth by deoxyguanosine and 1-beta-D-arabinofuranosylcytosine.

We studied the ability of 2'-deoxyguanosine (dGuo) to influence 1-beta-D-arabinofuranosylcytosine (ara-C) inhibition of soft agar cloning of the cultured human leukemia cell line K562. Ara-C alone inhibited cloning in concentrations of greater than 10 nM, with a steep drop in colony formation observed between 10 and 100 nM. dGuo and ara-C synergistically inhibited cloning; the combination of ineffective concentrations of dGuo (10-50 microM) and ara-C (less than or equal to nM) inhibited cloning by 40-70%. In K562 cells, dGuo is metabolized by both nucleoside kinase and purine nucleoside phosphorylase (PNP), resulting in augmentation of both the GTP pool (to more than 200% of control after a 3 hr incubation with 500 microM dGuo) and the dGTP pool (to more than 2700% of control after 3 hr with 500 microM dGuo). dGuo (50-500 microM) caused a decrease in the dCTP and dTTP pools and an increase in the dATP pool. Synergistic concentrations of dGuo plus 10 nM ara-C augmented the ara-CTP pool up to 800% of control after 3 hr to levels equivalent to those observed after incubation with 500 nM ara-C alone. Incorporation of 10 nM ara-CTP into DNA also increased in the presence of dGuo (up to a maximum of 300% of control), but only to a level that approximated the value observed with nM ara-C alone. The disparity between enlargement of the ara-CTP pool and augmentation of ara-C incorporation into DNA is consistent with the observation of Steinberg et al. [Cancer Res. 39, 4330 (1979)] that high concentrations of dGTP may inhibit DNA polymerase activity. Thus, synergy between dGuo and ara-C is multifactorial, possibly involving inhibition of DNA polymerase by elevated dGTP and ara-CTP pools and augmented incorporation of ara-C into DNA.

Cell Line↗

PubMed1984

Acute doxorubicin toxicity. Relationship to pretreatment liver function, response, and pharmacokinetics in patients with acute nonlymphocytic leukemia.

To determine if there is a relationship between development of acute doxorubicin toxicity, pretreatment liver function studies, and response, 64 acute nonlymphocytic leukemia patients undergoing induction chemotherapy with doxorubicin and cytosine arabinoside were evaluated. No statistically significant correlation could be found between the development of acute toxicity (mucositis) and the number or type of abnormal pretreatment liver functions. Patients receiving full doses of doxorubicin with mild hepatic dysfunction as determined by bromsulphalein (BSP) retention and serum liver function studies had the same incidence of toxicity and complete response rate as those with normal hepatic function. There was no significant difference between duration of response (P = 0.41) or survival (P = 0.17) between the two groups. Ten patients receiving a decreased dose of doxorubicin due to hepatic dysfunction had the same complete response rate but a lower incidence of toxicity as patients receiving full doxorubicin dose. Pharmacokinetic data from fluorescence plasma assays suggest no difference among patients with normal or mildly abnormal liver function studies receiving full doxorubicin doses. The results suggest that leukemia patients with mild hepatic dysfunction receiving a combination of full-dose doxorubicin and cytosine arabinoside for acute leukemia will have the same plasma pharmacokinetics, incidence of toxicity, and complete response rate as those with normal hepatic function. Reduction of doxorubicin dose in patients with abnormal liver function tests results in lower plasma concentrations, less toxicity, and the same response rate, but may also yield a shorter duration of response and survival.

Adolescent↗

PubMed1984

Reductive activation of mitomycin C and mitomycin C metabolites catalyzed by NADPH-cytochrome P-450 reductase and xanthine oxidase.

Under anaerobic conditions and with proper electron donors, NADPH-cytochrome P-450 reductase (EC 1.6.2.4) and xanthine oxidase (EC 1.2.3.2) similarly reductively metabolized mitomycin C. Reversed phase high performance liquid chromatography was used to separate, detect, and isolate several metabolites. Three metabolites were identified by mass spectrometry and thin layer chromatography as 1,2-cis- and trans-2,7-diamino-1-hydroxymitosene and 2,7-diaminomitosene. Three metabolites were phosphate-dependent, and two of them were identified to be 1,2-cis- and trans-2,7-diaminomitosene 1-phosphate. The amounts of the five identified metabolites generated during the reduction of mitomycin C varied with pH and nucleophile concentration. At pH 6.5, 2,7-diaminomitosene was essentially the only metabolite formed, whereas from pH 6.8 to 8.0, trans- and cis-2,7-diamino-1-hydroxymitosene increased in quantity as 2,7-diaminomitosene decreased. The disappearance of mitomycin C and the production of metabolites were enzyme and mitomycin C concentration-dependent. Substrate saturation was not reached for either enzyme up to 5 mM mitomycin C. Electron paramagnetic resonance studies demonstrated the formation of mitomycin C radical anion as an intermediate during enzymatic activation. Our results indicate that either enzyme catalyzed the initial activation of mitomycin C to a radical anion intermediate. Subsequent spontaneous reactions, including the elimination of methanol and the opening of the aziridine ring, generate one active center at C-1 which facilitates nucleophilic attack. Simultaneous generation of two reactive centers was not observed. All five primary metabolites were metabolized further by either flavoenzyme. The secondary metabolites exhibited similar changes in their absorbance spectra and were unlike the primary metabolites, suggesting that a second alkylating center other than C-1 was generated during secondary activation. We propose that secondary activation of monofunctionally bound mitomycin C is probably a main route for the bifunctional binding of mitomycin C to macromolecules and that the cytotoxic actions of mitomycin C result from multiple metabolic activations and reactions.

Animals↗

PubMed1984

Physicochemical characteristics of ferric adriamycin complexes.

Ferric ions and adriamycin in solution interact to form complexes that can yield colloidal and flocculant mixtures. At high concentrations (Fe3+ greater than or equal to 10(-4) M, adriamycin greater than or equal to 10(-5) M) an absorption appears at 600 nm, indicating colloid formation, which is directly responsive to concentrations of the reactants. Evidence from dilution experiments by spectral analysis, ultracentrifugation, titration, and filtration indicate that phase transition that is sensitive to pH and time occurs with iron-adriamycin complexes to yield flocculated drug. We conclude that patients and animals treated with the iron-adriamycin preparations known as 'quelamycin' received flocculated iron-adriamycin, which accounts for the toxic and pharmacologic effects reported. It may be useful to utilize colloidal preparations of reactive or irritating drugs to avert acute toxic effects and to produce slower release of active drug.

Chemical Phenomena↗

PubMed1984

The pharmacology of diaziquone given in intravenous or intracarotid infusion to normal and intracranial tumor-bearing puppies.

Diaziquone (also called "aziridinyl benzoquinone," or AZQ), an antitumor drug designed to penetrate the blood-brain barrier, has demonstrated activity against central nervous system (CNS) neoplasms. Four-hour infusions of carbon-14 (14C)-labeled AZQ (0.8 mg/kg) were given via the left common carotid artery or left brachial vein to two groups of puppies. A third group, harboring a transplantable canine glioma, received 14C-AZQ by intravenous infusion. Levels of chloroform (CHCl3)-extractable 14C (AZQ only) and total 14C (AZQ and metabolites) were determined in serial samples of plasma and cerebrospinal fluid (CSF). At the end of the infusion time, total and CHCl3-extractable 14C levels were determined in brain and tumor. Intra-arterial infusion of AZQ caused no histological abnormalities in the retina or brain. For the intravenous infusion group, the concentrations of CHCl3-extractable 14C (in nmol/ml or nmol/gm) were 0.68, 0.35, and 0.84 for plasma, brain, and CSF, respectively. For the intra-arterial infusion group, the concentrations were 0.25, 0.13, and 0.32 for plasma, brain, and CSF, respectively. Comparison of right and left hemispheres following intra-arterial infusion showed a slightly higher concentration of 14C in the ipsilateral (left) hemisphere, with concentrations (nmol/gm) of CHCl3-extractable 14C/total of 14C of 0.15/0.87 on the left and 0.12/0.65 on the right. Concentrations (nmol/gm) of CHCl3-extractable 14C/total 14C in brain and tumor were 0.60/1.24 and 0.58/1.65, respectively. In tumor-bearing animals, tumor and surrounding brain contained similar concentrations of AZQ, but there were higher concentrations of metabolites in tumor. This may reflect different metabolism of AZQ within brain and tumor or different permeability to metabolites. This study revealed that AZQ enters the CNS and brain-tumor tissue in substantial concentrations and that there is no significant advantage to intracarotid infusion of AZQ.

Animals↗

PubMed1984

Free radicals in quinone-containing antitumor agents. Electrochemical reduction of diaziquone (2,5-diaziridine-3,6-bis(carboethoxyamino)-1,4 -benzoquinone) and two analogues.

The one-electron electrochemical reduction of diaziquone was analyzed using electron spin resonance and compared to its enzymatic reduction. Two analogues were used to help the analysis. The analogues contained chlorine atoms which substituted either the carboethoxyamino groups or the aziridine groups of the parent compound. The diaziquone free radical produced electrochemically in dimethyl sulfoxide exhibited an 11-line electron spin resonance spectrum. The hyperfine couplings responsible for this spectrum were due to the aziridine nitrogens (aNAz), and the imide hydrogens (aHNHR) and nitrogens (aNNHR) of the carboethoxyamino groups. The couplings had the following order of strength: (aNAz) greater than (aHNHR) greater than (aNNHR). The nuclei responsible for the (aNAz) and (aHNHR) coupling were found to be magnetically inequivalent. Adding water to the dimethyl sulfoxide solution of electrochemically reduced diaziquone changed its 11-line ESR spectrum to a 5-line spectrum identical to the one observed for enzymatically reduced diaziquone. Hence, the identity of this latter free radical was resolved. Electrochemically reduced free radicals of antitumor agents can be used to understand biologically reduced ones and thus explore drug activity-free radical structure relationships.

Animals↗

PubMed1984

Interactions between cyclophosphamide and adriamycin metabolism in rats.

Rat liver microsomes under anaerobic conditions metabolize adriamycin (ADM) to 7-deoxyadriamycinol aglycone and 7-deoxyadriamycin aglycone. The metabolism of ADM and the concentration of cytochrome P-450 were not affected by preincubation with 2.76 mM cyclophosphamide. After preincubation of microsomes with 0.2 mM 4-hydroperoxycyclophosphamide, a prodrug of 4-hydroxycyclophosphamide, there was complete denaturation of the cytochrome P-450, and 22.8% inhibition of NADPH-cytochrome P-450 reductase. Under these conditions, the degradation of ADM was delayed (area under the concentration vs. time curve in micromolar X minutes: 15.6 +/- 2.4 for the controls, and 59.8 +/- 7.3 in the presence of 4-hydroperoxycyclophosphamide, P less than or equal to .005), 7-deoxyadriamycin aglycone increased progressively to reach a plateau at 20 min instead of showing a peak at 2 min and the formation of 7-deoxyadriamycinol aglycone was reduced. Microsomes from animals pretreated with cyclophosphamide (180 mg/kg i.p. once 4 days before sacrifice) showed a 24.0% reduction of NADPH-cytochrome P-450 reductase activity (P less than or equal to .02). This was accompanied by a decreased formation of 7-deoxyadriamycinol aglycone during the first 20 min of incubation (area under the concentration vs. time curve in micromolar X minutes: 68.0 +/- 15.7 in the controls, and 25.6 +/- 3.1 in the treated animals, P less than or equal to .005), whereas the formation of 7-deoxyadriamycin animals, P less than or equal to .005), whereas the formation of 7-deoxyadriamycin aglycone was not affected. These data indicate an interaction between the metabolism of cyclophosphamide and ADM in rats.

Alkylation↗