Pharmacokinetics of 14C-ambazone in rats.

In rats, the pharmacokinetics of 14C-ambazone after i.v. and oral administration was studied. The results demonstrate that the compound is incompletely absorbed from the gastrointestinal tract, penetrates rapidly and to a high degree into various tissues and is preferentially eliminated via the kidneys. After i.v. administration of 50 mg/kg b.m. disposition half-life in whole blood is about 6-7 h. The extent of absorption from the gastrointestinal tract is about 40%.

Rapid analysis for methylglyoxal bis(guanylhydrazone) by reversed-phase ion-pair liquid chromatography.

We describe a "high-performance" reversed-phase ion-pair liquid-chromatographic procedure for measuring methylglyoxal bis(guanylhydrazone) (MGBG) in plasma, urine, and bone-marrow leukocytes. Specimens of plasma and bone-marrow leukocytes are deproteinized with perchloric acid, then neutralized with KOH. Urinary MGBG is isolated by liquid-solid extraction in a C18 Sep-Pak. The chromatographic system consists of a 45 X 4.6 mm (i.d.) octadecylsilyl (C18, 5-microns particle) column and a mobile phase consisting of methanol/sodium acetate buffer (200 mmol/L, pH 4.5), 2/3, by vol. The acetate buffer also contains 20 mmol of 1-octanesulfonate and 40 mg of sodium azide per liter. The column effluent is monitored at 283 nm. At a flow rate of 3.0 mL/min, MGBG is eluted in 1.67 min. The detection limit is 20 nmol/L, and peak height varies linearly with concentration from 0.02 to 40 mumol/L. Analytical recovery exceeds 99%. Within-day CVs ranged from 0.9% to 2.9%, between-day CVs from 4.2% to 6.2%.

A gas chromatographic and mass spectral approach to the analysis of the anticancer drug methyl-G as the trimethylsilyl derivative.

Methyl-G was analyzed by gas chromatography and mass spectrometry after trimethylsilylation. A means of quantitatively measuring methyl-G by gas chromatography of the TMS derivative is presented using the analogous derivative of methylethyl-G as an internal standard. The value of this compound as an internal standard for measurements of methyl-G is discussed based on comparisons of the mass spectral and gas chromatographic properties of their derivatives as well as their similar behavior in the ion exchange method used for partial purification. The latter procedure is discussed in some detail, and the results of applying it to biological samples of human and cell culture origin are presented.

Pharmacokinetics of [14C]methylglyoxal-bis-guanylhydrazone) in patients with leukemia.

Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

Plasma levels and urinary excretion of methyl-GAG following iv infusion in man.

The pharmacokinetics of methyl-GAG was studied after nephrectomy in five patients with renal cell carcinoma and in one patient with breast cancer. Following rapid infusion (30 minutes) of 700 mg/m2 of methyl-GAG, terminal half-life of 136-224 hours. Drug levels declined to 6%-20% of the initial plasma concentration in the first 24 hours. Approximately 40% of the dose was recovered in the urine after 2 weeks. Extensive extravascular distribution of methyl-GAG is suggested.

Determination of methylglyoxal-bis(guanylhydrazone) in body fluids by ion-pair chromatography.

Methylglyoxal-bis(guanylhydrazone), Methyl-G, is a potent antineoplastic agent currently undergoing Phase l clinical trials. Serum, ascitic and pleural fluids, and urine are deproteinized with methanol, supernatant is evaporated, residue is redissolved in the eluent, lipids are removed with carbon tetrachloride, and an aliquot of the aqueous layer injected into the chromatograph. Ethylglyoxal-bis(guanylhydrazone) (Ethyl-G) is the internal standard. The mobile phase is a mixture of an aqueous buffer (containing 0.004 M heptane and pentane sulfonic acid, 90%:10%, buffered to pH 3.5) and methanol (68%:32%). The ion-pair complex is retained on a micro Bondapak C18 column, eluted with a flow of 2.0 mL/min. Absorbance is measured at 280 nm. Detectability: 30 ng/mL (0.11 micro M) in serum, ascitic and pleural fluids, 300 ng/mL (1.1 micro M) in urine. Calibration curves (peak height ratios of Methyl-G/Ethyl-G plotted against known drug concentrations) were linear in the 0.1-30 microg/mL range. Correlation coefficinets were 0.999; coefficients of variation for reproducibility were less than 5%. Residual blood levels of Methyl-G persist for several days. Methyl-G was found to pass into ascitic fluid.

High-performance liquid chromatographic assay for methylglyoxal bis(guanylhydrazone) (methyl GAG) in plasma and urine.

A clinically useful analytical method is described for monitoring both plasma and urine levels of methylglyoxal bis(guanylhydrazone) administered in the clinical management of certain neoplasms. The drug is initially separated from the biological matrix by retention on a small (2 cm) column packed with weak cation-exchange resin. The analyte is subsequently eluted quantitatively from the column with hydrochloric acid, and then separated and quantitated by paired ion high-performance liquid chromatography on an RP-18 column. The drug is detected to levels of 50 ng/ml of biological fluid by monitoring the column effluent spectrophotometrically at 280 nm. Absorbance was linearly related to drug concentration over the range 50 ng-50 microgram/ml of plasma or urine, and measurements could be made with a precision of +/- 4% over this range.