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After more than 20 years, the conflict of interest (COI) movement has failed to substantiate its central claim that interactions between physicians, researchers and the medical products industry cause physicians to make clinical decisions that are adverse to the best interests of their patients. The COI movement's instigators have produced no solid evidence of harm commensurate with their extravagant allegations. At the same time, they have diverted resources away from more worthwhile pursuits, such as basic and applied medical research, clinical care and medical education towards onerous compliance exercises and obtrusive laws. Perhaps worst of all, they have made it respectable to ignore the epistemological foundations of medical science, diverting attention away from the scientific merit of the information presented and focusing it instead on the identity and motives of those who present the information.

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The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m2 was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m2 over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially with the appearance of transient saturation kinetics in some and a mean t1/2 of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 microM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 microM and a terminal t1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was detected. Mean urinary excretion was: CP, 10.8; 4-OH, CP, 0.5; PM, 39.0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation coefficient of 0.859 (P < 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.

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Enzymatic degradation of phosphoramide mustard (PM), the ultimate cytotoxic metabolite of cyclophosphamide (CP), by the cleavage of the phosphorous-nitrogen (P-N) bond was investigated in vitro using 65,000g-soluble fractions from rat organ tissues. In the presence of physiologic bicarbonate in vivo, the P-N bond cleavage of PM was previously found to form 3-(2-chloroethyl)-1,3-oxazolidin-2-one (CNM), which is devoid of antitumor activity. This product was thus quantitated in the present studies using GC/MS and a deuterium-labeled analog (CNM-d8) as the internal standard. Under the experimental conditions, CNM was found to be enzymatically produced from PM in soluble fractions of rat liver, kidney, spleen, and intestine. Mean KM and Vmax values in soluble fractions of rat liver at pH 6.7 and 37 degrees C were determined to be 1.65 +/- 0.536 mM (N = 7) and 6.38 +/- 1.37 microM/min (N = 6), respectively. The enzymic activity of the rat liver soluble fraction was significantly reduced following boiling at 100 degrees C for 5 min. No CNM production was detected from PM incubated in plasma. The P-N bond cleavage for CP and for two other metabolites, 4-ketocyclophosphamide and alcophosphamide, was also investigated using soluble fractions from rat liver similar to that for PM. None of these compounds has been found to form CNM, however, indicating enzyme specificity for the P-N bond in PM. This enzyme probably resembles the previously described phosphamidases.(ABSTRACT TRUNCATED AT 250 WORDS)

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Pharmacokinetics of 4-hydroxycyclophosphamide (4-OHCP), the major active microsomal metabolite of cyclophosphamide (CP), were investigated in the Sprague-Dawley rat following separate iv bolus administrations of CP, synthetic 4-OHCP, and their combination. CP, 4-OHCP, and other metabolites such as phosphoramide mustard, alcophosphamide, and 3-(2-chloroethyl)-1,3-oxazolidin-2-one in rat plasma were simultaneously analyzed using GC/MS and stable isotope dilution techniques. Following iv administrations of 4-OHCP to rats at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg, phosphoramide mustard was found to be the major circulating metabolite followed by alcophosphamide and 3-(2-chloroethyl)-1,3-oxazolidin-2-one. No appreciable amount of nor-nitrogen mustard was detected in circulation. The mean excretion of unchanged 4-OHCP in two rats was 4.1 +/- 0.2% of the administered dose in 24-hr urine. Plasma concentration-time profiles of 4-OHCP declined monoexponentially with a mean half-life and total plasma clearance values of 8.1 min and 81.2 ml/min.kg, respectively. No dose-dependent kinetics were apparent between the 10 and 40 mg/kg doses used. The short half-life of 4-OHCP may be due partly to its degradation in plasma, which was found to be a first-order process in vitro with a half-life of 5.2 min. On the other hand, when CP was administrated to eight separate rats at 20 mg/kg each, the mean apparent elimination half-life for the derived 4-OHCP was 55.4 min as compared to 58.2 min, the mean elimination half-life for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)

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A sensitive and specific method for the quantitative analysis of 4-hydroxycyclophosphamide/aldophosphamide has been developed using gas chromatography-mass spectrometry and a deuterium-labeled analogue as the internal standard. The labile 4-hydroxycyclophosphamide/aldophosphamide and the internal standard in plasma were first converted into the more stable cyanohydrin adducts before extraction. The isolated adducts were silylated and the products analyzed by gas chromatography-mass spectrometry. The assay was found to be linear from 50 to 5000 ng/ml in plasma with a routine detection limit of 50 ng/ml. The within- and between-run standard deviations at 100 ng/ml on eight replicate determinations were found to be 6.2 and 11.9%, respectively. The extraction recovery was ca. 80%. This analytical method was used to evaluate the stability of 4-hydroxycyclophosphamide/aldophosphamide in fresh rat and pooled human plasma and to measure plasma 4-hydroxycyclophosphamide/aldophosphamide concentrations in the rat.

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Alcophosphamide was identified in urine obtained from Sprague-Dawley rats treated with a 1:1 mixture of cyclophosphamide and beta-(2H4)cyclophosphamide using chemical ionization mass spectrometry and the ion cluster technique. This compound was also quantified in rat plasma using gas chromatographic-mass spectrometry under ammonia chemical ionization following administration of cyclophosphamide. Apparent terminal half life of 76.2 +/- 13.7 min and area-under-the concentration-time curve value of 24.8 +/- 8.6 micrograms min/ml were obtained for derived alcophosphamide following iv bolus administration of cyclophosphamide. Following co-administrations of unlabeled and beta-(2H4)cyclophosphamide via iv/po and iv/ip routes, apparent terminal half-lives of 68.4 +/- 16.4 and 71.8 +/- 10.1 min were found for the iv portions and 106.7 +/- 25.2 and 73.9 +/- 5.2 min for the non-iv portions, respectively, for the derived alcophosphamide. Phosphoramide mustard was found to be a major circulating and urinary metabolite in the rat following iv administration of preformed alcophosphamide which gave a plasma half-life of 1.9 h.

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