Phase I and pharmacokinetic study of the P-glycoprotein modulator dexniguldipine-HCL.

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.

Bioavailability and pharmacokinetic characteristics of dexniguldipine-HCl, a new anticancer drug.

Dexniguldipine-HCl is a new dihydropyridine derivative with antineoplastic activity and potency for overcoming multidrug resistance. In this pharmacokinetic study the bioavailability of 3 doses of an oral formulation of dexniguldipine was to be determined. Fourteen patients with malignant disease not eligible for higher priority treatment and sufficient general condition were included. In 12 patients all pharmacokinetic investigations were available for evaluation. A single 4-h infusion of 2 mg per kg body weight of dexniguldipine was given as reference. Thereafter 3 increasing oral dosages (750, 1,500, 2,250 mg/d) were given on a 3-time daily basis for 3 consecutive weeks. On day 7 (under steady state conditions) of each period, a pharmacokinetic profile was done. Absolute bioavailability at the 3-dose levels was 3, 4, and 5%, respectively, thus slightly increasing with dose, but generally low. After intravenous administration terminal half life was 22.4 h, clearance 36.9 l/h and volume of distribution 1,193 1. Toxicity was tolerable with main adverse events being loss of appetite, nausea, and vomiting. Cardiovascular effects and a decrease in serum calcium were reported in several patients. Patients were allowed to continue treatment if a benefit was expected, and 2 patients showed tumor regression during treatment. One patient with renal cell carcinoma achieved a partial remission. Bioavailability of this oral formulation seems too low for routine clinical use, despite the fact that clinical effects have been observed.

High-performance liquid chromatographic determination of diltiazem and four of its metabolites in plasma. Application to pharmacokinetics.

A selective and very sensitive ion-pairing reversed-phase high-performance liquid chromatographic method has been developed for the simultaneous determination of diltiazem and four of its metabolites in plasma. The structurally related compound propionyl deacetyl-diltiazem was used as the internal standard and bromide was employed as the pairing ion. Plasma samples were extracted with methyl-tert.-butyl ether followed by back-extraction into 0.01 M hydrochloric acid and evaporation to dryness. High-performance liquid chromatographic analysis was carried out using C18-bonded silica and methanol-ammonium bromide-acetonitrile-triethylamine as the mobile phase. Using UV detection at 237 nm, the lower limit of detection in plasma was 0.1-0.2 ng/ml; calibration curves were linear between 1 and 800 ng/ml. The present assay procedure has been applied to monitoring plasma levels in intravenous and oral pharmacokinetic studies in several animal species and humans. The applicability of the new method could be confirmed by comparing plasma levels obtained by high-performance liquid chromatography with those obtained by gas chromatography.

[Behaviour of hydroxymethyl-methaqualone-glucuronide in hydrolysis with hydrochloric acid (author's transl)]. / Verhalten von 2'-Hydroxymethylmethaqualon-Glucuronid bei der Spaltung mit Salzsäure.

The behaviour of the glucuronide derivative of 2'-hydroxymethylmethaqualone with hydrochloric acid was investigated. Three methods of hydrolysis were selected. With method I(12-13% HCl; 30 min at 100 degrees C) about 27% and with method II (20% HCl; 6 min heated azeotrope in open vessel) about 94-95% of the glucuronide derivative was hydrolyzed. With method III (approx. 5% HCl; 30 min at 100 degrees C) only about 3% of the conjugated compound was converted to the free form.

[Behaviour of p-nitrophenol-glucuronide in hydrolysis with mineral acids (author's transl)]. / Verhalten von p-Nitrophenolglucuronid bei der Spaltung mit Mineralsäuren.

The behaviour of p-nitrophenol and synthetic p-nitrophenol-glucuronide with mineral acids has been investigated. With sulfuric acid (33%) about 93% of the glucuronide derivative have been hydrolysed; the solution was heated in open vessel for 15 sec. With hydrochloric acid (6%) only about 65% of the conjugated p-nitrophenol have been converted to the free form. No losses were detected, when free p-nitrophenol was treated under the same conditions. Three other methods of hydrolysis have been applied.

[The behaviour of codeine and codeine-6-glucuronide in hydrolysis with hydrochloric acid (author's transl)]. / Verhalten von Codein und Codein-6-glucuronid bei der Hydrolyse mit Salzsäure.

The behaviour of codeine and codeine-6-glucuronide with hydrochloric acid has been investigated. Three methods of hydrolysis were selected; they are often used in routine identification of drugs in urine. With method I (12--13% HCl; 30 min at 100 degrees C) about 53% of codeine-6-glucuronide were not hydrolized. The corresponding values: with method II (20% HCl; 6 min heated azeotrope in open vessel) about 8% and with method III (nearly 5% HCl; 30 min at 100 degrees C) about 83%.

[Isolation and identification of some metabolites of phenyramidol (Cabral) from human urine (author's transl)]. / Isolierung einiger Metaboliten des Phenyramidol (Cabral) aus menschlichen Harn und ihre Identifizierung.

The biological transformation of phenyramidol (I), some of which is also excreted unchanged, occurs by three main degradative pathways: 1. Hydroxylation of the pyridine ring in position 3 (metabolite V) and 5 (metabolite VI). 2. Cleavage of the ethanolamine chain with the formation of 2-aminopyridine (metabolite II) and presumably mandelic aldehyde. 3. Conjugation with glucuronic acid (metabolite III). Secondary reactions result in the production of: benzoyl carbinol (metabolite XV), benzoic acid (metabolite XI), mandelic acid (metabolite XII) and the glucuronides of V, VI, VII, XII and possibly II (metabolites VIII, IX, X, XIII and IV), all of which were also found as free, unconjugated compounds. A further, unusual reaction is the dimerisation of metabolite VI with the formation of a dipyridyl derivative (metabolite VII), which is excreted partly as the free compound, but mainly as the glucuronide (metabolite X). The occurrence of 2-(N-benzylamino)-pyridine (XIV) in the urine could not be explained. Four futher excretory products (metabolites XVI, XVII, XVIII and XIX) were not identified; XVI and XVII were extracted at an alkaline pH, whereas XVIII and XIX were extracted under neutral conditions. They could be detected both as free compounds, and after hydrolysis with HCl or alkali, but not after treatment with beta-glucuronidase.