W.J. van Oort

High-performance liquid chromatographic determination of the antitumor agent mitomycin c in human blood plasma

A high-performance liquid chromatographic method for the determination of the antitumor drug mitomycin C in blood plasma samples of cancer patients is described. The drug is extracted from the plasma with chloroform–2-propanol (1+1, ww) and chromatographed on a reversed-phase column with u.v. detection at 365 nm. The detection limit of the determination is 1 ng ml-1 for 0.2–1.0 ml plasma samples. Preliminary results of a pharmacokinetic study show that the sensitivity and selectivity of the assay are adequate for drug monitoring in clinical practice. The results obtained from multiwavelength detection suggest the existence of metabolites.

A sensitive high-performance liquid chromatographic method for determination of the anti-neoplastic agents vp 16-213 and vm 26 in biological fluids

Abstract A rapid and sensitive high-performance liquid chromatographic assay of the two antineoplastic podophyllotoxin analogs VP 16-213 and VM 26 in plasma and urine is described. The drugs are extracted, after adding an internal standard (ethyl ester of p -hydroxybenzoic acid) with an optimum amount of chloroform. After evaporation of the organic layer, the extracts are redissolved in the eluent and chromatographed on a Lichrosorb reversedphase C 15 column, with u.v. detection at 280 nm. Quantification is based on peak height ratios. The combination of an improved sample treatment and proper selection of chromatographic conditions results in a limit of determination of 30 ng of VP 16–213 or 50 ng of VM 26 per ml of plasma. Preliminary clinical pharmacokinetic results show that the sensitivity and selectivity of the assay are adequate for drug monitoring in clinical research.

Electrochemistry of podophyllotoxin derivatives: Part I. Oxidation mechanism of etoposide (VP 16–213)

The electrochemical oxidation of the antineoplastic agent etoposide in aqueous solution at a glassy carbon electrode shows an overall two electron transfer. At pH < 2.5, the oxidation proceeds in one voltammetric oxidation step. At pH ⩾ 2.5, the oxidation proceeds in two voltammetric oxidation steps. The first voltammetric oxidation step (peak i1) is a reversible 1 e− transfer resulting in a stable radical. The second step (peak i11) corresponds to the transfer of the second electron. The product formed after 2 e− oxidation is an unstable cation which undergoes rapid conversion into the orthoquinone. The orthoquinone has been isolated and characterized.

Polarographic analysis for corticosteroids: Part 1. The electroanalytical properties of corticosteroids

Abstract The electroanalytical behaviour of corticosteroids has been studied in different supporting electrolytes. The reduction patterns are established by examining pH profiles, by constant-potential coulometry, fast-sweep voltammetry, potentiometry with ion-selective electrodes and differential pulse polarography. Dimerization and alcohol formation take place with the reduction of the C-3 keto group resulting in one or two peaks, depending on the number of double bonds in the A-ring and the pH. The C-20 keto group is reduced to an alcohol. Both reduction steps can be used for analytical purposes. The differential pulse peak height is linear with the concentration down to 10 -6 M steroid.

Electrochemistry of potentially bioreductive alkylating quinones Part 1. Electrochemical properties of relatively simple quinones, as model compounds of mitomycin- and aziridinylquinone-type antitumour agents

The influence of methyl-, hydroxy and amino substituents on the electrochemical behaviour of simple 1,4-naphtho-and 1,4-benzoquinones, model compounds of many quinoid antitumour agents, in aqueous media was studied. Significant changes in electrochemical behaviour were observed, potentially the result of a change in the electron density of the quinone moiety, pre- or post-protonation of substituents, hydrogen bond formation, tautomerization reactions and steric interactions between the quinone moiety and substituents. The information obtained was of benefit in the elucidation of the reduction mechanisms of quinoid antitumour agents such as aziridnylquinones and mitomycins.

Effect of polishing the fluoride-selective electrode on the response time and sensitivity in flow systems

Abstract The lanthanum fluoride electrode is not very successful for monitoring fluoride in flow streams, e.g., from chromatographic processes, because of its slow response rate. Much faster responses are possible when mixtures of methanol and TISAB-II solutions containing 10−6 M fluoride are used as the carrier stream and when the electrode surfce is polished with very fine wet alumina powder. The flow cell was constructed in such a way that the diffusion film thickness was minimal. Flow streas injected centrally and perpendicular to the electrode surface and vry thin flows along the surface proved to be the best hydrodynamic configuration. With this set-up, response times of 2–6 s could be achieved in detecting concentration changes between 10−3 and 10−6 M fluoride.

Polarographic reduction and determination of nalidixic acid

Abstract Protonated and uncharged forms of nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid) ans its 7-hydroxymethyl derivative are reduced at the dropping mercury electrode in two one-electron waves, whereas their anions are reduced in a single one-electron wave. Reduction of nalidix acid results in hydrogenation of the ethylenic bond in the azinone ring. Protonated and uncharged forms of the propyl ester of the nalidix acid are reduced in a single one-electron wave. In acidic media, the CO bond in the 7-hydroxymethylnalidixic acid is also reduced. Structural effects on the properties of the acid—base equilibria are discussed. Based on these studies, a differential pulse polarographic method for the determination of 10 −5 –10 −6 M nalidixic acid and its metabolite, the 7-hydroxymethyl derivative, in urine was developed; only a simple extraction is needed.

In vitro and in vivo metabolism of VP 16–213 in the rat

A high-performance liquid chromatographic procedure utilizing u.v. and radioactivity detection was employed to examine the metabolism of the epipodophyllotoxin derivative VP 16-213 by the rat in vivo and in liver extracts and subcellular fractions. VP 16-213 has been shown to be metabolized extensively by rat liver homogenates and rat liver microsomes, with the formation of one major metabolite. The metabolite formed in vitro was the only metabolite present in plasma samples of rats treated with i.p. injections of VP 16-213. Based on its chromatographic and solubility characteristics, the metabolite is probably a cis- or trans-hydroxy acid derivative. The liver is involved in the metabolism of VP 16-213, and the localization of the enzyme(s) responsible for the formation of the major metabolite is in the microsomal fraction.

Polarographic analysis for corticosteroids: Part 3. Determination of Corticosteroids in Single-Component Tablets

The differential pulse polarographic determination of Corticosteroids in single-component tablets is described. The active compounds are extracted from the excipients with a solvent with similar lipophilicity as the polarographic solvents, with a yield of about 100%. The corticosteroid esters and alcohols are determined by standard addition methods. The standard deviations range from 0.5 to 2.5% depending on the excipients and on the method of extraction.

Electrochemistry of podophyllotoxin derivatives: Part II. Oxidation of teniposide and some epipodophyllotoxin derivatives

Oxidation of the anions of teniposide (I) and its aglycone (III) occurs over the pH range from 3 to 12 in two one-electron waves. The loss of the first electron yields a radical, the second a phenoxenium ion. The latter is converted by nucleophilic attack involving hydroxide ions into an ortho-quinone. In the cis-hydroxy acids derived from teniposide (IIa) and etoposide (IIb), the oxidation occurs at pH < 9.5 in a single two-electron step. This difference in behaviour is attributed to a facilitated oxidation of the radical formed in the first electron transfer of the open chain compounds. The primary products of the two-electron oxidation of the hydroxy acids IIa and IIb undergo chemical transformations which do not involve the formation of an ortho-quinone. The difference in reactivity of the product of the one-electron oxidation between the lactones (I, III) and the corresponding hydroxy acids (IIa, IIb) results in the two-electron oxidation of hydroxy acids in the physiological pH range, and in the formation of a relatively stable radical in solutions of the lactones. The absence of a stable radical as well as the impossibility of an ortho-quinone in solutions of the hydroxy acids may be responsible for the smaller antineoplastic activities of these open chain compounds when compared to the corresponding lactones.