A pharmacokinetic study of high-dose metoclopramide suppositories.

The pharmacokinetics of high-dose rectal metoclopramide have been studied in nine patients after administration of 150-mg suppositories. The results have been compared to the pharmacokinetics of the drug in five patients who received the same dose of metoclopramide intravenously. Administration of a metoclopramide suppository achieved plasma drug concentrations that are associated with the effective treatment of cytotoxic drug-induced nausea and vomiting. In three patients who received the drug by both routes the systemic availability of the suppository appeared to be complete. High-dose metoclopramide suppositories are convenient and may be advantageous in the treatment of medical oncology out-patients.

A comparison of absorption rate models in the prediction of steady-state plasma concentrations during oral theophylline administration.

During therapy with oral controlled released theophylline/aminophylline, steady-state plasma drug concentrations may be predicted by fitting estimates of patient pharmacokinetic parameters to a pharmacokinetic model. The choice of model requires an assumption about the type of rate reaction of the drug absorption process (zero order or first order). In 10 subjects, plasma theophylline concentrations after a single intravenous dose of aminophylline were used to make individual estimates of drug clearance and volume of distribution. Each subject then received oral controlled release theophylline ('Theo-Dur', Fisons Pharmaceuticals plc) and steady-state pre-dose and post-dose plasma concentrations were determined. Predictions of steady-state plasma theophylline concentrations using pharmacokinetic models based on first-order (Model A) and zero order (Model 01) drug absorption were compared. Model A and Model 01 each underestimated the pre- and post-dose steady-state plasma drug concentrations. However, Model 01 was more accurate in predicting post-dose drug concentrations, whilst Model A demonstrated better precision in the prediction of pre-dose drug concentrations at steady-state (P less than 0.05).

Stimulation of p-nitrophenylphosphatase activity of mung bean shoot extracts. Preliminary observations as a possible screening test for anticonvulsant drugs.

The p-nitrophenylphosphatase (pNPPase) activity of mung bean shoot extracts has similar characteristics to that of animal tissue. Mung bean shoot pNPPase activity is maximal between pH 7.8 and 8.2 and at a substrate concentration between 10 and 20 mM and is inhibited by sodium ions. Mung bean shoot pNPPase activity is competitively inhibited by ATP with a Ki value of 2.8 mM. A wide range of anticonvulsant drugs tested all stimulated the pNPPase activity of the mung bean shoot extracts. The nonanticonvulsant drugs tested did not have this effect, with the exception of pemoline, which, although not acknowledged to be an anticonvulsant drug, did show anticonvulsant activity when tested using conventional methods involving animals. In double-blind trials, 12 out of 15 compounds were correctly classified as anticonvulsants or nonanticonvulsants. It is proposed that the pNPPase activity of mung bean shoot extracts may be useful as a preliminary screen for anticonvulsant drugs.

Antipyrine elimination in saliva after low-dose combined or progestogen-only oral contraceptive steroids.

1 A 'low-dose' combined oral contraceptive steroid (OCS) preparation containing 30 microgram ethinylo-estradiol and 150 microgram levonorgestrel was found to reduce significantly antipyrine clearance in a group of women acting as their own controls. 2 An OCS preparation containing only a progestogen (75 microgram norgestrel) did not reduce antipyrine clearance in a second group of women. 3 The evidence suggesting that the oestrogen component of combined OCS preparations could be responsible for the reduction in antipyrine clearance is discussed.

PIP: This study investigates the ability of a single preparation of either the low-dose combined or progestogen-only type of oral contraceptives (OCs) to alter antipyrine elimination in 2 groups of women. 6 patients aged 22-28 were given a low-dose combined OC preparation containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel; 12 patients aged 18-41 were given a preparation containing only a progestogen, 75 mcg norgestrel. Antipyrine elimination kinetics was setermined during the menstrual cycle, and at 11 weeks for the 1st group, and at between 11-14 weeks for the 2nd group, in saliva samples. There was a significant reduction of 29% in antipyrine clearance in the 1st group, and no significant change in antipyrine elimination in the 2nd group. These results are in agreement with previous published results; it is possible that the estrogen component of combined OC preparations could be responsible for the reduction in antipyrine clearance. If it is confirmed that progestogen-only OCs are without effect on antipyrine elimination, then it does imply that the concern that the elimination of any drug which is metabolized by liver microsomal enzymes will be impaired when the drug is administered with an OC is not applicable to progestogen-only preparations.

Effects of drug pretreatment on antipyrine elimination in the rabbit.

Iproniazid (25-100 mg/kg) produced a marked, dose-related reduction in antipyrine elimination in the rabbit, whereas reductions produced by nitrazepam (32 mg/kg) or SKF 525A (25 and 40 mg/kg) were small. Phenobarbitone, 10 mg/kg chronically, increased antipyrine elimination. The small inhibitory effect of SKF 525A on antipyrine metabolism in the rabbit was unexpected compared to the marked effect in the rat.

Antipyrine estimations in the rabbit using gas--liquid chromatography: a reliable method for studying factors affecting oxidative drug metabolism.

The application of a gas--liquid chromatographic (GLC) method to measurements of antipyrine in plasma for the estimation of antipyrine half-life (T1/2) in the rabbit is described and is compared with previous GLC methods. It has been established that the estimation of antipyrine can be achieved with acceptable precision and that rabbits can act as their own controls in the study of factors that might alter T1/2. Iproniazid phosphate, 50 mg/kg IP, was shown to produce a mean increase of 170% in T1/2.

Halothane-induced sleeping time in the mouse: its modification by benzodiazepines.

The conditions under which prolongation of halothane-induced sleeping time in the mouse may be used as a test for centrally acting drugs are described. The test can be recommended for its practical advantages over methods using barbiturates to induce hypnosis; due cognizance must be taken of a diurnal variation in the response of mice to halothane. To assess the usefulness of the test the effects of amphetamine, chlorpromazine, histamine, morphine, nikethamide, pentobarbitone and SKF 525A have been investigated. The interaction between 5 benzodiazepines and halothane has been studied in particular. Results from sleeping time experiments, measurements of body temperature and of brain halothane concentrations suggest that the halothane-benzodiazepine interaction is due to additive CNS depressant effects. It was found that nitrazepam and diazepam were clearly more potent than chlorodiazepoxide, medazepam and oxazepam in respect of their interactions with halothane.

Some observations on the mechanism of benzodiazepine-barbiturate interactions in the mouse.

1 The prolongation of pentobarbitone sleeping by five benzodiazepines, administered by prior intraperitoneal injection, was measured in mice. The pentobarbitone was injected either intraperitoneally or intracerebroventricularly. For each benzodiazepine, the prolongation was dose-related and differences in potency between benzodiazepines were not marked. 2 The percentage prolongation of sleeping times produced by most of the benzodiazepines was greater when the pentobarbitone was given intracerebroventricularly and was explained by a preferential addition of CNS depressant effects associated with this route. 3 To test whether the action of intraperitoneally administered pentobarbitone had been influenced by a metabolic component, the effects of nitrazepam on drug metabolism, measured by changes in plasma phenazone levels in the mouse, were studied. Nitrazepam (32 mg/kg, i.p.) produced a 23% reduction in the rate of phenazone metabolism. 4 Nitrazepam was also shown to have produced a transient fall in body temperature. Calculations based on Q10 values suggested that this hypothermia accounted, at most, for half the metabolic change measured.