Sai Y. Chang

Kinetics of intravenous melphalan

We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High‐pressure liquid chromatography and 14C‐melphalan were used to assay drug concentration in plasma and urine. Composite plasma t½β was 7.7 ± 3.3 and t½β was 108 ± 20.8 min for 8 of the patients. The mean 24‐hr urinary excretion of melphalan was 13.0 ± 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured 14C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein‐bound activity). These data and evidence of rapid disappearance from plasma at 37° in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t½β of melphalan in vivo.

Oral melphalan kinetics

The systemic availability of melphalan after oral administration is not well known. Most patients are put on a fixed oral dosage regimen. We have studied the disposition of melphalan in 14 patients after single oral doses. Five were also studied after receiving the same dose intravenously. Oral melphalan had a mean plasma terminal phase half‐life (t½) of 90 ±17 min. The mean area under the plasma concentration: time curve (CXT) was 53 ± 33 µg · min/ml. Urinary excretion of oral melphalan averaged 10.9 ± 4.9% during the first 24 hr. The CXT ratio (oral: intravenous) for the 5 patients studied after both oral and intravenous melphalan (0.6 mg/kg) ranged between 0.25 and 0.89 and averaged 0.56. After oral dosing in 14 fasting patients, the time at which melphalan first appeared in the plasma varied between 15 min and 6 hr. In a myeloma patient who took oral melphalan, no melphalan was found in plasma or urine up to 24 hr. Some instances of failure of tumor response to oral melphalan may be due to inadequate bioavailability rather than inherent tumor resistance.

Pharmacokinetics and metabolism of chlorambucil in man: a preliminary report

Summary A sensitive and specific gas-chromatographic-mass spectrometric (GC-MS) assay for chlorambucil and its major metabolite in biological fluids, phenylacetic acid mustard, has been developed. It has been applied to the study of oral chlorambucil pharmaco-kinetics in 6 patients. The assay has a sensitivity limit of 50 ng/ml and a precision of 94.3±1.3% at a plasma chlorambucil concentration of 200 ng/ml. In vitro chlorambucil recovery is temperature dependent with recovery rate constants at 37°C of k = 0.43 hr−1 for water and k = 0.12 hr−1 for plasma. After an oral bolus dose of 0.6–1.2 mg/kg in 4 patients the mean terminal phase half-life of chlorambucil was 91.7±19.3 min, its mean peak plasma concentration, 1.1±0.6 μg/ml (adjusted to a dose of 0.6 mg/kg) and its mean plasma concentration-time product, 143±102 μg min/ml (adjusted to a dose of 0.6 mg/kg). The urinary excretion of chlorambucil over the first 24 h was 0.54±0.16% and its mean renal clearance was 0.029±0.014 ml/min/kg. The hepatic extraction of chlorambucil in these 4 patients averaged 0.24±0.13. The mean phenylacetic acid mustard plasma terminal phase half-life was approximately 1.6 times greater than that of its parent compound. The mean 24 h metabolite urinary excretion was 0.29±0.16%. This preliminary pharmacokinetic data suggests that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance, and that it is almost completely metabolized, having extremely low urinary excretion.

In vitro degradation of l-phenylalanine mustard (l-PAM)

Summaryl-Phenylalanine mustard (l-PAM), a bis-choroethylamine, is an important drug in the treatment of multiple myeloma and ovarian cancer. It undergoes rapid hydrolysis in vitro and in vivo, forming the mono-and dihydroxy degradation products. l-PAMs first-order disappearance rate in a phosphate-buffered solution did not differ statistically according to the presence or absence of activated rat liver microsomal enzymes. Furthermore, l-PAMs disappearance rate in a rat whole liver perfusion system was not greater than its hydrolysis rate in water. In vitro plasma recovery studies showed that up to 85% of the 14C l-PAM drug equivalents could be recovered as the parent compound and the mono-and dihydroxy degradation products. Thus, l-PAM in in vitro degradation was similar qualitatively and quatitatively to its reported in vivo degradation in animals and man. It is concluded that l-PAM does not undergo important, active in vivo metabolism.

The stability of L-phenylalanine mustard in bile

Abstract L-phenylalanine mustard (L-PAM) was incubated at 37° C in bile of bovine, canine and human origin. Recovery rate constants of L-PAM from bile were 0.1/hr for canine bile (0–3 hours); 0.18/hr for bovine bile; 0.45/hr for human bile. No significant hydrolysis of L-PAM in canine bile was noted for the period of 3 to 6 hours at 37° C. The incubation of L-PAM in sodium taurocholate solution (1000 molar excess) gave a recovery rate constant 0.15/hr at 37° C. However, the incubation of L-PAM in bilirubin solution (2.5 mg/ml H 2 O) gave a recovery rate constant of 0.52/hr at 37° C. The high concentration of the parent compound L-PAM seen in vivo in canine bile after i.v. administration may be related to its low in vitro degradation rate in canine bile.

Pharmacokinetics of bleomycin in man: III. Bleomycin 57Co Vs Bleomycin

SummaryOf all the bleomycin-containing radiopharmaceuticals, bleomycin 57Co has proven the most useful whole-body tumor-imaging agent. We have studied its in vitro physicochemical properties and in vivo disposition in animals and man to optimize its use as a scanning agent. High-pressure liquid chromatographic analysis of the standard bleomycin 57Co preparation (1 unit bleomycin plus 1 mCi chloride 57Co showed it to contain 1% free chloride 57Co). Dialysis experiments showed that bleomycin 57Co does not dissociate as it diffuses through a dialysis membrane. In nine patients, bleomycin 57Co had a t12/βof 3.4 h, a t12/γof 45.8 h, a Vd of 12.1 liters/m2 and a 24-h urinary excretion of 82.1% of the administered dose. In comparison, bleomycin, assayed by radioimmunoassay, had a terminal phase plasma t1/2 of only 4.0 h, a similar Vd (17.3 liters/m2), and a 24-h urinary excretion of only 44.8%. Bleomycin 57Co tumorto-plasma concentration ratios ranged from 14.1–23.8 at 1 day to 5.4 at 2 days after administration. Our finding that tumor imaging with bleomycin 57Co is best achieved at 24 h is well explained by its almost complete urinary elimination in the first few hours after administration and the peak tumor-to-plasma ratio achieved at 24 h. One disadvantage of bleomycin 57Co as a scanning agent is its very extended plasma t1/2 In rabbits chloride 57Co has the same prolonged plasma terminal elimination phase (t12/γ) as our standard bleomycin 57Co preparation, which contains chloride 57Co as a 1% impurity. Removal of this impurity prior to scanning or use of cold cobalt chloride to help eliminate it from the plasma might result in a shortened bleomycin 57Co plasma t12/γ.

Covalent adduct formation and chloroform production after free radical attack on fatty acids by carbon tetrachloride reactive intermediates

The interactions of fatty acids and the trichloromethyl free radical generated anaerobically by the benzoyl peroxide model system were studied. Chloroform was produced due to the interaction of the trichloromethyl free radical with the unsaturated fatty acid ester methyl oleate, indicating the hydrogen in chloroform may result from abstraction from fatty acids. In addition, chloroform was detected in incubations containing the saturated fatty acid ester methyl stearate, indicating hydrogen abstraction is not limited to allylic hydrogens. Mass spectral analysis identified one adduct resulting from additional reactions to methyl oleate, and an adduct resulting initially from hydrogen abstraction on methyl stearate. These findings describe previously unreported reactions of the trichloromethyl free radical with saturated fatty acid, and inhibition of chloroform production by 3 free radical inhibitors.

Concentration profile for the dissolution of drug tablets undergoing simultaneous degradation

An empirical approach to the concentration-time history of a dissolving drug has resulted in a cube-root equation in which the characteristic constant of the equation embodies the important physical variables of the system. This expression has been used to study the dissolution of a drug that degrades simultaneously in the test solution. An alternative representation of the dissolution process is first-order kinetics. These two approaches are compared by fitting the experimental data of the dissolution of digoxin and melphalan tablets in various media, and a new method for the proper analysis of data for the dissolution of tablets that simultaneously degrade in the test solution is presented.