Pharmacokinetics and toxicity of oral (-)-(S)-bromofosfamide in lung cancer patients.

The pharmacokinetics and toxicity of (-)-(S)-bromofosfamide ((2S)-(2-chloroethylamino)-3-(2-bromoethyl)-1,3,2-oxazaphosphorinae 2-oxide, CAS 146452-37-1, CBM-11) were determined in ten patients with non-small cell lung cancer following an oral dose of 1.38 g/m2 B.S.A. (Body Surface Area). The drug was given as a powder in gelatine capsules to fasting patients. Plasma samples were collected during the first 24 h after administration. All samples, after extraction with chloroform, were assayed by a reverse phase HPLC method using UV detection at 200 nm. Orally administered (-)-(S)-bromofosfamide showed relatively fast absorption kinetics. Peak concentration of 47 micrograms/ml was observed after 1 h. The average half-life was about 5 h. Toxicities associated with oral (-)-(S)-bromofosfamide therapy consisted of symptoms regarding the central nervous system, gastrointestinal tract and urinary tract. Neurotoxic symptoms were the most common clinically significant side effects and probably dose limiting.

Pharmacokinetics of (-)-(S)-bromofosfamide after intravenous and oral administration in mice.

(-)-(S)-Bromofosfamide ((2S)-(2-chloroethylamino)-3-(2-bromoethyl)-1,3,2-oxazaphosphorinane 2-oxide, CAS 146452-37-1, CBM-11) is a new potential anti-cancer drug, currently under investigation. Its pharmacokinetics and bioavailability were studied in female mice following intravenous and oral administration of the dose of 50 mg/kg. The compound was extracted from plasma samples using chloroform and analyzed by high-performance liquid chromatography with UV detection at 200 nm. Orally administered (-)-(S)-bromofosfamide was absorbed quickly, attaining a maximum level of 33.9 micrograms/ml at 5 min, and was eliminated with a half-life (t1/2) of about 0.9 h. The average half-life of intravenously administered (-)-(S)-bromofosfamide was about 0.7 h. The total plasma clearance (CL) and volume of distribution (Vd) were found to be 0.14 l/h and 4.92 l/kg, respectively. The absolute bioavailability of (-)-(S)-bromofosfamide after oral administration was 105%.

High-performance liquid chromatographic analysis for the determination of domperidone in human plasma.

A specific and sensitive high-performance liquid chromatographic method for the determination of domperidone in human plasma is described. Domperidone was isolated by solid-phase extraction using nitrile SPE cartridges. The drug was eluted with a mixture consisting of methanol-triethylamine-acetic acid, separated on a reversed-phase column, and measured by fluorimetric detection after post-column photoderivatization. The absolute extraction recovery from plasma samples was 83%. The limit of quantitation was established as 1 ng/ml. The relative standard deviation of the determination of plasma levels by this method over the standard curve concentration range was less than 10%, expect with the concentration of 1 ng/ml. The suitability of the method is shown for pharmacokinetic studies.

A bioequivalence study of two brands of glipizide tablets.

In this open, randomized, two way crossover, bioequivalence study, two 5 mg tablet preparations of glipizide (Glipizyd tabl. 5 mg, Tarchominskie Zaklady Farmaceutyczne POLFA S.A., and Glibenese tabl. 5 mg, Pfizer), were compared in 24 healthy male volunteers. Pharmacokinetic variables (mean maximum plasma concentration, mean time to reach maximum plasma concentration, and the mean area under the plasma concentration-time curve) were not statistically significantly different for the two formulations. It can be concluded that the two tablet preparations of glipizide are likely to be bioequivalent.

High-performance liquid chromatographic analysis for the determination of buspirone analogue--mesmar in rat plasma.

A simple and selective analytical method for the determination of buspirone analogue--mesmar in rat plasma is described. The procedure involves liquid-liquid extraction followed by reversed-phase high-performance chromatographic analysis with UV detection at 245 nm. No endogenous compounds were found to interfere. The absolute extraction recovery from plasma samples was 76%. The linearity was assessed in the range 0.12-2.44 nmol/ml. Stability of mesmar during processing (autosampler) and in plasma was checked. This method proved suitable for pharmacokinetic studies following single oral dose in rats.

Induction of cytochromes P4502B1/2B2 by some antiepileptic drugs in rat liver.

The effects of phenobarbital (PB), carbamazepine (CBZ) and diazepam (DZ) on total hepatic cytochrome P450, cytochromes P4502B1/2B2 contents and aminopyrine N-demethylase activity was investigated. Adult male rats were treated per os with PB (80 mg/kg/day), CBZ (75 mg/kg/day) or DZ (90 mg/kg/day) for 3 consecutives days. Carbamazepine and phenobarbital produced significant increase of the contents of total cytochrome P450 and cytochromes P4502B1/2B2 as well as aminopyrine N-demethylase activity. In contrast, diazepam decreased the total hepatic cytochrome P450 content. This drug did not affect the level of cytochromes P4502B1/2B2 but increased aminopyrine N-demethylase activity comparing to the control animals.

Effect of carbamazepine on cytochromes P4502B 1/2B2 in rats exposed to high environmental temperature.

The combined effect of carbamazepine (CBZ) and raised environmental temperature on total hepatic cytochrome P450 and on cytochromes P4502B1/2B2 contents was investigated. Carbamazepine produced significant increase of the contents of total cytochrome P450 and cytochromes P4502B1/2B2 in rats exposed to 21 degrees C and 28 degrees C. In contrast exposure of rats of 35 degrees C decreased induction capacity of carbamazepine.

High-performance liquid chromatographic analysis for the determination of miconazole in human plasma using solid-phase extraction.

A high-performance liquid chromatographic method for the determination of miconazole in human plasma is described. A solid-phase extraction was performed on an octadecyl (C18) cartridge. Miconazole was eluted with methanol, separated on a reversed-phase column and was measured by ultraviolet detection at 230 nm. The absolute extraction recovery from plasma samples was 85%. The limit of detection was established as 5 ng/ml. The coefficient of variation of the determination of plasma levels by this method over the standard curve concentration range was less than 10%, except with the concentration of 10 ng/ml. The plasma levels of miconazole in twelve healthy volunteers given a 250-mg oral dose of two tablet forms were determined by this method.

Activity of glutathione-dependent enzymes in long term diabetes. I. Activity of glutathione S-transferase and glutathione peroxidase in the liver of alloxan induced diabetic rats.

Cytosolic liver glutathione S-transferase (GST) activity was decreased for CDNB and DCNB as substrates in long term alloxan induced diabetes. Similar to cytosolic, microsomal glutathione S-transferase activity was also decreased for CDNB. In contrast, both microsomal and cytosolic GST activities for ETA as well as cytosolic and microsomal glutathione (GSH) contents were unaffected. The activity of Se-dependent glutathione peroxidase activity, but not nonSe-dependent peroxidase activity was increased in diabetic rats. The results suggest that diabetic state has a different effect on each isoenzyme of hepatic glutathione S-transferase activity. After insulin treatment of diabetic animals the activities of both cytosolic and microsomal GST was not restored and the activity of non Se-GSHPx was significantly lower than the control value.

Activity of glutathione-dependent enzymes in long term diabetes. II. Glutathione contents and activity of glutathione-dependent enzymes: S-transferase and peroxidase in the kidney cytosol of alloxan induced diabetic rats.

In the kidney of diabetic rats the elevated GSH concentration was accompanied with the 25% increase of cytosolic Se-dependent glutathione peroxidase (Se-GSHPx) activity. The activity of cytosol glutathione S-transferase (GST) was decreased to 55% of the control with p-nitrobenzyl chloride, and was unchanged with 1-chloro-2,4-dinitrobenzene, and ethacrynic acid. The activity of GST with cumene hydroperoxide (a good substrate for determination the activity of non Se-GSHPx) in diabetic animals stay unchanged too. Insulin treatment of diabetic rats restores the normal glycemia and the body weight, strongly reduces glucosuria and reverses the morphological changes observed in the kidney. The activity of GST and cytosol Se-GSHPx, as well as GSH content, returned to a normal values after insulin treatment, while the activity of non Se-GSHPx was reduced of about 50% in relation to the control values.

The effect of short-term alloxan-induced diabetes on the activity of drug metabolizing enzymes.

Chemical diabetes produced in male rats by treatment with alloxan (45 mg/kg) decreased aminopyrine N-demethylase activity but not hepatic microsomal protein, cytochrome P-450 and cytochrome b5 contents. In contrast, diabetes increased aniline hydroxylase activity. Glutathione S-transferase activity and the most of the forms of UDP-glucuronyltransferase were decreased but phenolsulphotransferase activity was not affected in alloxan-induced rats. These results suggest that observed changes may led to alteration of drug metabolism and toxicity in diabetes.

Induction of microsomal drug metabolizing enzymes by phenobarbitone in the rats exposed to increased environmental temperature.

Exposure of rats for 3 consecutive days (6 h a day) to 28 degrees C or 35 degrees C does not lead to changes in the induction of hepatic microsomal cytochrome P-450 associated monooxygenases by phenobarbitone as compared with control animals exposed to 21 degrees C. These results suggest that environmental temperature does not change the capacity of phenobarbitone to induce drug metabolizing enzymes in rat liver.

Effects of benzodiazepines on enzymes metabolizing drugs. IV. Effect of diazepam and oxazepam on hepatic microsomal drug metabolizing enzymes in rats exposed to high environmental temperature.

Administration of diazepam or oxazepam caused a different response of the rat hepatic microsomal cytochrome P-450 dependent monooxygenase system. Both drugs produced significant decrease in the activity of NADH: cytochrome c oxidoreductase in rats exposed to 21 degrees C, but not to 28 degrees C and 35 degrees C, and did not change the activity of aniline hydroxylase, aminopyrine N-demethylase and 4-nitroanisole O-demethylase and cytochrome b5 level at any tested temperatures. Oxazepam, but not diazepam, caused a decrease in cytochrome P-450 content in rats exposed to 21 degrees C only. The results indicate that the high ambient temperature modifies the effect of tested benzodiazepines on the activity of some microsomal enzymes.

[Benzodiazepines as cytochrome P-450 and cytochrome b5 inductors in rat liver microsomes]. / Benzodiazepiny jako induktory cytochromu P-450 i cytochromu b5 w mikrosomach watroby szczurów.

Among the benzodiazepines tested (diazepam, oxazepam, clonazepam, nitrazepam and chlordiazepoxide ) chlordiazepoxide is the most potent inducer of cytochrome P-450, diazepam is a poor inducer, whereas clonazepam and nitrazepam do not possess a capacity to induce of cytochrome P-450. On the other hand, microsomal cytochrome b5 is induced by diazepam only. The extent of induction of cytochrome P-450 and cytochrome b5 depends on the environmental temperature. Chlordiazepoxide is the most potent inducer of cytochrome P-450 in rats exposed to an ambient temperature of 28 degrees C, whereas diazepam have the highest induction ability in rats exposed to 35 degrees C. On the other hand, nitrazepam increased the content of cytochrome b5 in rats exposed to temperature of 35 degrees C only; diazepam was the most potent inducer of cytochrome b5 in rats exposed to temperature of 21 degrees C. These results indicate that high ambient temperature is a factor modifying the ability of benzodiazepines to induce of microsomal cytochrome P-450 and cytochrome b5.

[Structure and effects of benzodiazepines on hepatic microsomal monooxygenases in rats exposed to environmental temperature]. / Struktura benzodiazepin a ich dzialanie na mikrosomalne monooksygenazy watroby szczurów w podwyzszonej temperaturze otoczenia.

Five benzodiazepines (diazepam, oxazepam, clonazepam, nitrazepam and chlordiazepoxide) were compared with respect to their capacity to affect microsomal aniline hydroxylase, aminopyrine N-demethylase and 4-nitroanisole O-demethylase of rats exposed to the high ambient temperature of 28 degrees C or 35 degrees C. We have stated that the highest effect on the microsomal enzyme activities was observed after chlordiazepoxide, clonazepam or nitrazepam treatments. These results indicate that the presence of nitro group at position 7 or N-oxide at position 4 of benzodiazepine is important for the ability of benzodiazepines to affect the hepatic microsomal enzymes. High environmental temperature modifies the effect of benzodiazepines on tested microsomal enzymes.

[Effect of benzodiazepines on enzyme-metabolizing drugs. III. Activity of microsomal monooxygenases in the rat liver exposed to chlordiazepoxide and elevated environmental temperature]. / Dzialanie benzodiazepin na enzymy metabolizujace leki. III. Aktywnosc mikrosomalnych monooksygenaz watroby szczura w nastepstwie dzialania chlordiazepoksydu i podwyzszonej temperatury otoczenia.

It has been stated that elevation of environment temperature to 28 degrees C or 35 degrees C modifies effects of chlordiazepoxide on activities of rat liver microsomal enzymic systems involved in metabolism of xenobiotics: amidopyrine, aniline and 4-nitroanisole++.

Effects of phenobarbitone and short-term exposure to heat on microsomal cytochrome P-450 and associated monooxygenases in rat liver.

Short-term exposure of the control and phenobarbitone-treated rats to high ambient temperature caused a different response of the hepatic microsomal cytochrome P-450-dependent monooxygenase system participating in the oxidation of aniline, aminopyrine and p-nitroanisole. The highest differences of the enzyme activities were observed in rats exposed to 28 degrees C, as compared with animals exposed to 21 degrees C or 37 degrees C.