The dependence of paracetamol absorption on the rate of gastric emptying

1. The rate of gastric emptying was measured directly in 14 convalescent hospital patients and paracetamol absorption was studied following an oral dose of 1.5 g.2. Rapid gastric emptying was associated with the early appearance of high peak plasma paracetamol concentrations whereas peak concentrations were low and occurred late when gastric emptying was slow.3. There was a significant correlation between the rate of gastric emptying and the 0-4 and 0-24 h urinary excretion of paracetamol and its metabolites.4. In five patients with abnormally slow gastric emptying the mean maximum plasma concentration and 0-4 and 0-24 h urinary excretion of paracetamol were significantly lower than in seven patients with normal gastric emptying rates while the time taken to reach maximum plasma concentrations was longer.5. Individual differences in the rate of gastric emptying may contribute to variable absorption of many drugs.     

Effect of intravenous atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate in young and fit elderly volunteers.

1. The effects of atropine on gastric emptying, paracetamol absorption, salivary flow and heart rate were examined in young and elderly subjects. 2. Seven healthy young male subjects of age 23 +/- 1.3 years (mean +/- s.e. mean) and seven fit elderly subjects of age 70 +/- 1.6 years received placebo (P), 300 micrograms atropine (A300) or 600 micrograms atropine (A600) in randomized order at weekly intervals. After 10 min they ingested a 500 ml orange drink containing 1 g paracetamol. Gastric emptying was measured by ultrasound, blood samples were taken to measure plasma paracetamol concentration by h.p.l.c., salivary flow was measured by dental cotton wool cylinder technique and pulse rate was recorded. 3. In young subjects, the gastric 5 min volumes were 260.1 +/- 17.9 ml (s.e. mean) with P, 310.6 +/- 10.5 ml with A300 and 317.9 +/- 8.9 ml with A600. In elderly subjects, the gastric 5 min volumes were 166.7 +/- 10.1 ml with P, 252.6 +/- 13.7 ml with A300 and 266.0 +/- 14.8 ml with A600. Thus the early adaptive phase of gastric emptying was more rapid in the elderly than the young with all treatments (P less than 0.05). The gastric emptying half-lives were 18.8 +/- 2.5 min with P, 30.0 +/- 2.7 min with A300 and 34.5 +/- 3.3 min with A600 in young subjects (P less than 0.01). In elderly subjects, the gastric emptying half-lives were 16.1 +/- 2.5 min with P, 23.7 +/- 2.4 min with A300 and 30.0 +/- 2.9 min with A600 (P less than 0.01). Thus atropine intravenously in therapeutic dose (300 and 600 micrograms) delayed gastric emptying in both young and elderly subjects. The inhibitory effect of atropine on the early adaptive phase of gastric emptying appeared to be greater in the elderly. The maximum plasma concentration (Cmax) of paracetamol was greater in the elderly than young with all treatments (P less than 0.05). There was a close relationship between the early adaptive phase of gastric emptying and paracetamol absorption (P less than 0.05). Atropine reduced salivary flow and increased resting heart rate in both young and old subjects. The effect of atropine on salivary flow was greater in the elderly. 4. The dose-response relationship varied in the three systems (stomach, salivary glands and heart rate) studied. Age had an effect on the magnitude of the response, but not on the slope of the dose-response curve for the two doses of atropine studied.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring

The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug.Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC_{0–4 h} for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC_{0–4 h} was significantly increased (5.6 g · ml^–1 · h vs 4.5 g · ml^–1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC_{0–4 h} ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65).These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.     

The effect of pirenzepine on gallbladder emptying in humans

The effect of the selective antimuscarinic agent, pirenzepine, on gallbladder function was studied in six healthy volunteers, using 99mTc HIDA (N-[2,6-diethylthenyl] carbamoylmethyl iminodiacetic acid) hepatobiliary scanning. Pirenzepine, in doses that inhibit gastric acid secretion, did not alter gallbladder emptying responses to sham feeding stimulation or to a test meal.     

The relationship between gastric emptying of semisolids and paracetamol absorption.

The relationship between gastric emptying rate of semisolid Tc-99m labelled Chelex-100 resin/oatmeal and paracetamol absorption was determined simultaneously in seven healthy volunteers. There was no significant correlation between the half-time of gastric emptying and the time of the peak serum paracetamol concentration. There was no significant correlation between the area under the serum paracetamol concentrations at 60 and 90 min and the % meal emptied in 60 and 90 min respectively. Three subjects showed a lag phase in gastric emptying pattern, while the other four showed the emptying curves without evidence of a delayed phase of emptying. Individual values of gastric emptying determined by the methods varied widely.     

A comparison of serum and saliva paracetamol concentrations.

The relationship between serum and saliva paracetamol concentrations was investigated in twenty healthy volunteers. The plasma and saliva drug concentrations showed a significant correlation (r = 0.67). However the agreement between the two methods of measurement was poor with limits of agreement of -15.3 mg l-1 to +15.9 mg l-1 with mean sample values of 19.2 and 19.5 mg l-1 for plasma and saliva, respectively.     

The influence of gastric emptying on droxicam pharmacokinetics

Droxicam is a new nonsteroidal anti-inflammatory drug that is a pro-drug of piroxicam. The influence of gastric emptying rate on droxicam pharmacokinetics has been investigated in eight healthy male volunteers. A single, 20 mg dose was administered p.o. together with 1500 mg of paracetamol. Gastric transit was experimentally modified by administration of propantheline (45 mg, p.o.) or metoclopramide (10 mg, i.v.) simultaneously with the droxicam and the paracetamol. Plasma levels of paracetamol were used as markers of gastric transit. The plasma concentrations of piroxicam, the active substance from droxicam, were determined by a high-performance liquid chromatographic method. The pharmacokinetic parameters of droxicam were: Cmax = 1.03 +/- 0.16 micrograms/mL (mean +/- SD). Tmax = 11.1 +/- 5.7 hr, AUC = 115.7 +/- 29.6 micrograms hr/mL, T 1/2 a = 2.64 +/- 0.72 hr. T 1/2 el = 73.6 +/- 16.7 hr, CL/F = 3.06 +/- 0.80 mL/min and MRT = 111.1 +/- 23.5 hr. Following modification of gastric emptying, only Tmax (droxicam + metoclopramide = 25.0 +/- 10.8 hr and droxicam + propantheline = 20.8 +/- 8.8 hr) underwent significant change (P less than 0.05). These results indicate that absorption rate of droxicam has been modified but bioavailability does not suffer modification in conditions of altered gastric emptying.     

The effect of probenecid on paracetamol metabolism and pharmacokinetics

Summary The influence of probenecid on the pharmacokinetics of paracetamol was investigated in a group of healthy volunteers.Pretreatment with probenecid caused a significant decrease in paracetamol clearance (6.23 to 3.42 ml·min^–1·kg^–1). The urinary excretion of paracetamol sulphate (243 to 193 mg); and paracetamol glucuronide (348 to 74.5 mg) were significantly reduced, whereas that of paracetamol was unchanged.Probenecid was shown to be an uncompetitive inhibitor of paracetamol glucuronidation in vitro, using rat liver microsomes.     

Delay of gastric emptying by duodenal intubation: sensitive measurement of gastric emptying by the paracetamol absorption test

AIMS: To examine the influence of duodenal intubation on gastric emptying measured by the paracetamol absorption test using a new algorithm developed to estimate emptying parameters, and to determine the sensitivity of this test. METHODS: A caloric liquid meal with paracetamol as marker of emptying was administered orally to eight healthy volunteers during phase I and phase II of the migrating motor complex (MMC) and without intubation on 3 separate days, and to 10 patients with partial gastrectomy. RESULTS: Healthy subjects: With duodenal tube, time until 25% of the meal had emptied (t25%) was 24+/-7 (phase I, P<0.02) and 21+/-6 min (phase II, P<0.02) compared with 14+/-4 min for meal intake without intubation. Time until 50% of the meal had emptied (t50%) was 45+/-8 (phase I, P<0.001) and 35+/-8 min (phase II, P<0.02) compared with 26+/-9 min for meal intake without intubation. Intraduodenal instillation of 10-20 mL of the liquid meal was reliably detected. Patients: In 9 out of 10 patients with partial gastrectomy t25% was below the lower limit of the range for healthy controls, and t25% detected accelerated emptying with a higher degree of sensitivity than the commonly applied pharmacokinetic parameters Cmax and Tmax. CONCLUSIONS: A duodenal tube delays gastric emptying of a caloric liquid meal. The paracetamol absorption test emerges as a sensitive method suitable for detecting both delayed and accelerated gastric emptying of caloric liquid meals.     

The effect of metoclopramide on neonatal gastric emptying.

1 The effect of metoclopramide on gastric emptying was studied on twenty-five occasions in fifteen low birth weight babies. 2 The serial test-meal technique was used. 3 The results indicate that metoclopramide does not promote gastric emptying in the newborn period.     

Lack of effect of paracetamol on the pharmacokinetics of chloramphenicol.

The effect of oral paracetamol (1 g) on the pharmacokinetics of oral chloramphenicol (500 mg) was examined in five adult male Zimbabwean patients with normal hepatic and renal function. No significant alteration of half-life, area under the concentration-time curve or peak concentration of chloramphenicol was observed. The previously reported, potentially serious interaction between chloramphenicol and paracetamol administered intravenously was not observed with the more commonly used oral preparations.     

The influence of gastric emptying on plasma concentrations of the analgesic, meptazinol.

1. The influence of gastric emptying on the rate of absorption and peak plasma concentrations of meptazinol was studied in monkeys by comparison of the plasma concentrations of the drug achieved after intragastric and intraduodenal administration of the compound. Absorption was much more rapid and plasma concentrations were very much higher after intraduodenal than after intragastric dosage. 2. Determination of the 'normal' gastric emptying time in rats and monkeys showed that this was much longer in the monkey than in the rat. In addition, meptazinol was shown to have a pronounced retarding action on gastric emptying in the monkey, an effect which was not apparent in the rat. 3. The significance of these observations in relation to the species difference in oral potency of the drug is discussed.     

The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice

Aims To evaluate the effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in plasma, gastric juice and saliva following intravenous infusion or oral dosing of metronidazole. Methods Eight volunteers received single doses of metronidazole (400 mg) intravenously and orally, whilst taking placebo or omeprazole (40 mg, twice daily for 5 days) in a randomized 4-way crossover study. Metronidazole and hydroxymetronidazole concentrations in plasma, saliva and gastric juice samples were determined by h.p.l.c. Pharmacokinetic parameters for metronidazole and hydroxymetronidazole were calculated, and the significance of the mean differences in parameters between omeprazole and placebo co-administration was assessed using a two-tailed, paired t-test. Results There were no significant differences (P<0.05) in any of the plasma or saliva pharmacokinetic parameter values for metronidazole between volunteers receiving omeprazole or placebo when metronidazole was administered either as an intravenous infusion or orally. Following intravenous administration of metronidazole to the placebo group and omeprazole treated group respectively, the gastric transfer of metronidazole was significantly reduced from 15.5±10.4% to 2.6±1.0% of the dose (P=0.007; 95% CI of difference 4.8 to 21.0) with concomitant changes in the metronidazole AUC (from 77.5±18.0 μmol l⁻¹ h to 352.6±182.1 μmol l⁻¹ h; P=0.0003; 95% CI of difference 127.6 to 422.7), C_max (from 61.4±26.5 μmol l⁻¹ to 271.8±104.3 μmol l⁻¹; P=0.0001; 95% CI of difference 118.6 to 302.1). Similarly, the gastric juice AUC of hydroxymetronidazole was significantly reduced from 3.2±1.9 μmol l⁻¹ h to 1.5±0.8 μmol l⁻¹ h of the dose (P=0.0043; 95% CI of difference 0.4 to 3.0) with a concomitant change in C_max (from 5.0±2.5 μmol l⁻¹ to 3.0±1.2 μmol l⁻¹; P=0.0007; 95% CI of difference 0.7 to 3.4). Conclusions Omeprazole had little effect on the plasma and salivary pharmacokinetics of metronidazole (or its hydroxymetabolite) after intravenous or oral administration, but it did have a substantial effect on the pharmacokinetics of metronidazole and hydroxymetronidazole in gastric juice.     

The effect of oxytocin on basal and pethidine-induced delayed gastric emptying.

1. Continuous infusion of oxytocin (0.33 u min-1) accelerated gastric emptying of semisolid TC-99m labelled Chelex-100 resin/oatmeal in 10 healthy volunteers under basal conditions. 2. Administration of oxytocin did not change the pattern of gastric emptying delayed by pethidine. 3. The emptying pattern of semisolid has confirmed the existence of a lag phase.     

Antroduodenal motility and gastric emptying. Gastroduodenal motility and pH following ingestion of paracetamol

The influence of paracetamol on antroduodenal motility and gastric pH was studied in 11 healthy subjects and the relationship between gastroduodenal motility and gastric emptying rate time, tmax, to peak concentration of serum paracetamol, Cmax, was evaluated. The incidence of antral phase III activity and the duration of phase III was diminished with paracetamol (P less than 0.05). The other motility parameters assessed were unchanged. Three patterns of motility and absorption were observed. One group (n = 5) were fast absorbers with a tmax of 1 h and a motility pattern characterized by antral activity, a high motility index and a short duration of phase II (33-60 min); the phase IIIs were complete except in one case. The second group (n = 4) had tmax at 1.5 h and their phase II motility was characterized by a longer duration (80-133 min) (P less than 0.05), by antral activity, and by a high motility index; their phase IIIs were all incomplete. The last group (n = 2) were slow absorbers: Cmax was not reached in the investigation period, no antral contractions were seen, and the motility index was low. The area under the serum-concentration curve of paracetamol differed between the groups at 90 and 180 min (P less than 0.01).     

The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam

Summary The effects of the benzamide cisapride (C) (8 mg) i.v. have been compared to placebo (P) in a double blind randomised study. The effects on gastric emptying, the absorption and effects of oral diazepam, and BP and pulse were observed.Cisapride increased the rate of gastric emptying of 500 ml liquid containing diazepam 10 mg (t_1/2 C: 7.4 min, P: 14.9 min). The initial rate of absorption of diazepam contained in the drink was increased by C (AUC 0–1 h C: 328 µg h 1^–1, P: 253 µg h 1^–1, but there was no change in overall bioavailability. This change in diazepam kinetics was associated with a significantly greater impairment in reaction time in the first 45 min after drinking but not in self rated sedation. Cisapride produced a significant tachycardia (e.g. after 10 min C: 82 beats/min, P: 69 beats/min) which probably reflects a peripheral vasodilator action. Cisapride may therefore alter the pharmacokinetics and dynamics of concurrently administered drugs.     

The effect of polycarbophil on the gastric emptying of pellets

The influence of the putative bioadhesive, polycarbophil, on the gastric emptying of a pellet formulation, has been investigated in three fasted subjects. The pellets were radiolabelled with technetium-99m. Gastric emptying was measured using the technique of gamma scintigraphy. The pellets emptied from the stomach rapidly and in an exponential manner. Polycarbophil did not retard the gastric emptying of the pellets.     

Influence of simulated weightlessness on the oral pharmacokinetics of acetaminophen as a gastric emptying probe in man: a plasma and a saliva study

This study evaluated the effect of simulated weightlessness on gastric emptying, using acetaminophen as a probe and -6 degrees head-down bed rest to simulate zero gravity. Eighteen volunteers were given 1 g of acetaminophen orally before the bed rest and at days 1, 18, and 80. Cmax, tmax, AUC0- infinity, AUC0-t, and t1/2 were calculated for plasma and saliva. The plasma Cmax showed a significant increase (10.43 microg/mL [day 1] to 14.74 microg/mL [day 80]), while tmax significantly decreased (1.41 h [day 1] to 0.91 h [day 80]). Similar results were obtained with saliva, and there were significant increases in the AUCs. The good correlation between the plasma and saliva data suggests that saliva sampling can be valid for acetaminophen pharmacokinetics. The changes in Cmax and tmax indicated more rapid drug absorption, which could have been as a result of faster gastric emptying or an increased blood flow to the intestine.     

The effect of nicotine on the delay of gastric emptying

The effect of cigarette smoking and its active component, nicotine, on the gastric emptying of solid food was assessed in a randomized double-blind crossover design. Ten regular smokers were studied after a 6 h fast and least 18 h after their last cigarette. Subjects smoked a total of three high (1.91 mg) or low (0.17 mg) nicotine cigarettes, before and after a technetium-labelled solid meal and were scanned by gamma camera periodically over a 2-h period. All calculations of gastric emptying revealed a significant delay after smoking high versus low nicotine cigarettes in: mean per cent isotope remaining in the stomach at each measurement point from 90-120 min; amount of meal remaining in the stomach at 2 h; and mean time at which 50% of the meal had emptied (T1/2). Delay in gastric emptying was significantly correlated with increase in serum nicotine concentration on the high nicotine day.     

Comparison of the inhibitory effect of three antimuscarinic drugs: pirenzepine, atropine and propantheline on acid secretion and gastric emptying in the conscious rat

The present investigation was carried out to compare the effects of pirenzepine, a novel antimuscarinic drug, with those elicited by atropine and propantheline on gastric acid secretion and gastric emptying in the conscious rat. The administration of all three drugs resulted in a dose-related inhibition on both parameters that at large doses was nearly total. Comparison of the ID50 ratios for each antagonist on gastric emptying versus acid secretion showed that pirenzepine was unique in that it selectively inhibited acid secretion. Its potency on acid secretion was about 15 times higher than that elicited on gastric emptying. The results are compatible with the proposed existence of two different classes of gastric muscarinic receptors mediating secretory and motor activities.