The pharmacokinetics of single doses of metoclopramide in renal failure

Summary The pharmacokinetics of metoclopramide have been studied after intravenous and oral dosing (10 mg) to 6 patients with chronic renal failure. The mean terminal half-life was 13.9 h after intravenous and 14.8 h after oral administration. Total body clearance after i. v. dosing was 16.7 l/h. Oral bioavailability was 71.8%. In comparison to previous studies on normal subjects these results indicate that clearance of metoclopramide in renal failure is approximately 30% of normals. This difference is not accounted for by the change in renal clearance and suggests impaired metabolism or an alteration in enterohepatic circulation of metoclopramide in renal failure.     

Oral bioavailability of high-dose metoclopramide

Summary The oral bioavailability of high-dose metoclopramide was studied in 12 patients, who received oral or intravenous (i.v.) metoclopramide in random order with each of 2 consecutive courses of cytotoxic chemotherapy. The terminal half-life of metoclopramide was 7.1±0.4 h (mean±SEM) and was not affected by the route of drug administration. Mean bioavailability was 86.6±4.7% and the range (65–118%) was less than that reported for standard doses. Neither half-life nor bioavailability was significantly correlated with age. Adverse effects were mild and were similar for both oral and iv metoclopramide. Oral high-dose metoclopramide, given in the same doses as for i.v. administration, should therefore be as effective as the i.v. regimen and may be easier to administer.     

Stereoselective disposition of carvedilol in man after intravenous and oral administration of the racemic compound

The racemic compound carvedilol is a multiple-action oral antihypertensive drug that exhibits both vasodilator and non-selective beta-adrenergic blocking activities. The effects of the levorotatoryS-enantiomer [S( – )-CARV] are vasodilatation and beta-blockade. TheR (+)-enantiomer [R (+)-CARV] is a pure vasodilating agent. Quantitative determination of the enantiomers in human plasma by HPLC was carried out after formation of diastereoisomers with the chiral reagent 2,3,4,6-tetraO-acetyl--d-glucopyranosyl isothiocyanate (GITC). The pharmacokinetics of the enantiomers were studied following i. v. (12.5 mg in 1 h) and p. o. (50 mg) administration of racemic carvedilol in ten healthy male subjects according to a randomized crossover design. The AUCs ofS (–)-CARV were significantly lower than those ofR (+)-CARV after both i. v. and p. o. administration. The systemic clearance of the two enantiomers was significantly different, whereas half-lives and apparent distribution volumes were comparable. Following p. o. administration, the absolute bioavailability (31.1% and 15.1%, respectively) and maximal plasma concentrations ofR (+ )-CARV were twice those ofS (–)-CARV A similar difference was found in the half-lives. A close correlation existed between enantiomeric ratios after i.v. and after p. o. administration, demonstrating slight intraindividual variability. The preferential systemic clearance of theS ( – )-enantiomer suggests stereoselective hepatic metabolism of carvedilol, becoming especially apparent after p. o. administration. The small intrasubject variability in enantiomer ratios indicates a relatively constant relation of beta-blockade to vasodilation during chronic treatment.     

Antiemetic effect and pharmacokinetics of high dose metoclopramide in cancer patients treated with cisplatin-containing chemotherapy regimens

Summary Fifteen cancer patients receiving cisplatin-containing chemotherapy participated in two antiemetic studies. In Study 1 they received standard antiemetics in low doses on demand, and in Study 2 the same patients participated in an open randomized cross-over study between metoclopramide 1 and 2 mg/kg i.v.×5.Serum metoclopramide was determined by HPLC. Self-reporting of nausea using a visual analogue scale (VAS) was compared with observer rated scores. Tolerability and volume vomited were assessed by nurse observers.The biological half-life of metoclopramide was 9.9 h, the volume of distribution was 9.9 l/kg and the clearance was 0.68 l/h/kg. The pharmacokinetics of high dose metoclopramide was linear in the range 0.15–2 mg/kg×5, with very little accumulation.Compared to standard antiemetics, both high dose regimens of metoclopramide had a significant effect on nausea, but no effect on the volume vomited. Self reports of nausea were significantly correlated with observer rated values. Tolerance of high dose metoclopramide was good except in 3 patients who left the study because of restlessness and trismus.It is concluded that high dose metoclopramide probably can be administered for several consecutive days without appreciable accumulation of the drug. Self-reporting of nausea by patients on VAS is a simple and feasible method of evaluation. The finding that metoclopramide affects nausea but not vomiting supports the hypothesis that nausea and vomiting should be evaluated separately in assessing antiemetic efficacy.     

Oral absorption and presystemic first-pass effect of chlorpheniramine in rabbits

The oral absolute bioavailabilities of chloropheniramine (CPM) in four rabbits (New Zealand White, male, mean wt. 3.71 kg), averaged 0.06±0.03, 0.11±0.08, and 0.09±0.01 following a 3, 10.5, and 21 mg/kg dose, respectively. The individual bioavailability data and the AUCof one of the demethylated metabolites, desdimethyl CPM (DDCPM) obtained following different doses suggested the existence of saturable presystemic elimination. Two rabbits received an additional 10.5 mg/kg dose of CPM through portal vein infusion. Based on the oral, intraportal vein and i.v. studies, the mean extraction ratios of gut and the liver calculated for these two rabbits averaged 0.58 and 0.76, respectively. The latter value agreed well with the estimated hepatic extraction ratio from the in vitro liver homogenate study (0.89) or from the i.v. studies (0.83). The extensive prehepatic first-pass effect observed in the present study was consistent with similar findings in humans and dogs.     

Impaired cimetidine absorption due to antacids and metoclopramide

Summary In 8 healthy subjects the absorption of cimetidine was investigated when given alone, together with 60 ml aluminium/magnesium hyroxyde containing antacid (neutralising capacity 26 mmol HCl/10 ml), and together with liquid metoclopramide 14 mg. The antacid significantly (P<0.01) reduced the bioavailability (area under the plasma level-time curve) of cimetidine, on average by one third. Metoclopramide also reduced the bioavailability by an average of 22%. The reductions were associated with significantly reduced excretion of cimetidine in urine. There was no change in the half-life or renal clearance of cimetidine, supporting the hypothesis of reduced gastrointestinal absorption. The results indicate that cimetidine and antacids should not be given together, and that the dose of cimetidine may have to be increased if it is administered concomitantly with metoclopramide.     

Pharmacokinetic interaction between fluoxetine and metoclopramide in healthy volunteers

The pharmacokinetic interaction of fluoxetine with metoclopramide in healthy volunteers was evaluated. A dose of 20 mg metoclopramide in combination with 60 mg fluoxetine was administered to 24 healthy male volunteers in a two treatment study design, separated by 8 days in which the fluoxetine alone was administered as a single p.o. dose daily. Plasma concentrations of metoclopramide were determined during a 24 h period following drug administration. Metoclopramide plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of metoclopramide were calculated using non-compartmental analysis. In the two periods of treatment, the mean peak plasma concentrations (Cmax) were 44.02 ng/ml (metoclopramide alone) and 62.72 ng/ml (metoclopramide after pre-treatment with fluoxetine). The times taken to reach Cmax and tmax, were 1.15 h and 1.06 h, respectively. The total areas under the curve (AUC(0-infinity)) were 312.61 ng.h/ml and 590.62 ng.h/ml, respectively. The half-life values (t1/2) were 5.52 h and 8.47 h. Statistically significant differences were observed for both AUC(0-infinity) and t1/2 of metoclopramide when administered alone or after 8 days treatment with fluoxetine. The experimental data demonstrate the pharmacokinetic interaction between fluoxetine and metoclopramide and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed.     

Single-dose pharmacokinetics and safety of iptakalim hydrochloride in Chinese healthy volunteers

Objectives To investigate the safety, pharmacokinetics and food effect of iptakalim in healthy adult Han Chinese volunteers. Methods Study 1 was a randomized open‐label, Latin square designed, single‐dose, three‐period, self‐control crossover study. Six men and six women received 5, 10 and 20 mg of iptakalim orally. Study 2 was a randomized, open‐label, single‐dose, two‐period, self‐control crossover study. Ten men were included and each subject received 5 mg iptakalim orally, fasting and nonfasting. Key findings No adverse effects were reported and no clinically meaningful changes in vital signs were found. Cmax, AUC_0–t and AUC_0–∞ were proportional over the dose levels of 5, 10 and 20 mg. Tmax, t½ and CL/F were similarly independent of dose level. In the 5 mg and 20 mg group, the Cmax, AUC_0–t and AUC_0–∞ in women were significantly higher than in men, although they showed no difference after correction by mg/kg doses in the 5 mg group. At the 5‐mg dose level, no significant difference in pharmacokinetics was found in nonfasting and fasting subjects. Conclusions Single‐dose pharmacokinetics of iptakalim showed dose proportionality over the dose levels of 5–20 mg. The pharmacokinetics showed gender differences in the 5 and 20 mg groups. Food had almost no impact on the pharmacokinetics at the 5 mg level.     

Effect of high-fat, high-protein, and high-carbohydrate meals on the pharmacokinetics of a small dose of ethanol

Aims To investigate whether the relative amounts of fat, carbohydrate (CHO), or protein in a meal influence the pharmacokinetics of a small dose of ethanol. Methods Nine healthy men received ethanol (0.30 g kg⁻¹ body weight) on five occasions in a randomized cross-over fashion. On three occasions the dose of ethanol was consumed within 15 min of eating a standardized breakfast of similar volume and calorific value but containing different amounts of fat, CHO, and protein. On two other occasions the same dose of ethanol was ingested on an empty stomach (overnight fast) or administered by intravenous (i.v.) infusion over 30 min. Results The blood-ethanol profiles showed large inter and intraindividual variations, especially when ethanol was ingested after eating food. The peak blood-alcohol concentrations (BAC) were 16.6±4.0, 17.7±7.1, and 13.3±4.0 mg dl⁻¹ (mean±s.d.) after fat, CHO, and protein-rich meals and 30.8±4.3 and 54.3±6.4 mg dl⁻¹ after fasting and i.v. infusion, respectively. The corresponding areas under the concentration-time profiles (AUC) were 1767±549, 1619±760, 1270±406 mg dl⁻¹ min after fat, CHO, and protein-rich meals compared with 3210±527 and 4786±446 mg dl⁻¹ min after fasting and i.v. infusion, respectively. The time required to eliminate ethanol from the blood was shortened by 1–2 h in the fed-state. Conclusions Drinking ethanol after eating a meal, regardless of the nutritional composition, decreases the systemic availability of ethanol. Because gastric emptying is slow and more prolonged with food in the stomach, the delivery of ethanol to the duodenum and the liver will be highly variable as will the hepatic clearance of ethanol. Provided that portal venous BAC remains fairly low and ethanol metabolizing enzymes are not fully saturated then part of the dose of ethanol can be cleared by hepatic first-pass metabolism (FPM), as one consequence of Michaelis-Menten elimination kinetics.     

General Treatment of the Enterohepatic Recirculation of Drugs and Its Influence on the Area Under the Plasma Level Curves,Bioavailability, and Clearance

A general treatment of enterohepatic recirculation of drugs has been developed based on the fraction of drug in systemic circulation that is excreted in the bile and the fraction of drug reabsorbed from the gut that reaches systemic circulation in each enterohepatic cycle. The deduced equations make it possible to establish mathematical relationships between the areas under the blood level curves (AUC) of a drug when administered to normal and bile duct-cannulated animals and to predict the effect of enterohepatic recycling on bio-availability and clearance. The results were compared with those obtained by other authors using different approaches to enterohepatic recirculation, and some discrepancies were found in the equations describing the effect of enterohepatic recycling on AUC and bioavailability of drugs. The cause of such discrepancies and the problems associated with the prediction of hepatic extraction ratio from in vitro studies are discussed.     

Effects on cimetidine bioavailability of metoclopramide and antacids given two hours apart

Summary Plasma cimetidine levels were determined in 9 normal subjects after a single oral dose of cimetidine 400 mg under control conditions, 2 h before metoclopramide 20 mg and 2 h after a potent antacid. The bioavailability of cimetidine was not significantly affected by metoclopramide and it was marginally reduced by the antacid.     

Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride

AIMS: To examine the influence of cisapride on the pharmacokinetics of ethanol and the impact of gastric emptying monitored by the paracetamol absorption test. METHODS: Ten healthy male volunteers took part in a cross-over design experiment. They drank a moderate dose of ethanol 0.30 g kg-1 body weight exactly 1 h after eating breakfast either without any prior drug treatment or after taking cisapride (10 mg three times daily) for 4 consecutive days. In a separate study, the same dose of ethanol was ingested on an empty stomach (overnight fast). Paracetamol (1.5 g) was administered before consumption of ethanol to monitor gastric emptying. Venous blood was obtained at 5-10 min intervals for determination of ethanol by headspace gas chromatography and paracetamol was analysed in serum by high performance liquid chromatography (h.p.l.c.). Results The maximum blood-ethanol concentration (Cmax ) increased from 3.8+/-1.7 to 5.6+/-2.3 mmol l-1 (+/-s.d.) after treatment with cisapride (95% confidence interval CI on mean difference 0.28-3.28 mmol l-1 ). The area under the blood-ethanol curve (AUC) increased from 6.3+/-3.5 to 7.9+/-2.6 mmol l-1 h after cisapride (95% CI -0. 74-3.9 mmol l-1 h). The mean blood ethanol curves in the cisapride and no-drug sessions converged at approximately 2 h after the start of drinking. Both Cmax and AUC were highest when the ethanol was ingested on an empty stomach (Cmax 9.5+/-1.7 mmol l-1 and AUC 14. 6+/-1.9 mmol l-1 h), compared with drinking 1 h after a meal and regardless of pretreatment with cisapride. CONCLUSIONS: A small but statistically significant increase in Cmax occurred after treatment with cisapride owing to faster gastric emptying rate as shown by the paracetamol absorption test. However, the rate of absorption of ethanol, as reflected in Cmax and AUC, was greatest after drinking the alcohol on an empty stomach. The cisapride-ethanol interaction probably lacks any clinical or forensic significance.     

The pharmacokinetics of α-methyldopa in dogs

-Methyldopa was intraarterially and orally administered to dogs at two dose levels in a randomized complete crossover design. The appearance of secondary peaks in the plasma concentration-time profiles indicated the presence of enterohepatically recycled methyldopa. This was established by the absence of a secondary peak following readministration of a dose after biliary cannulation and the detection of methyldopa in the bile of a cannulated dog. Enterohepatic recirculation was estimated to account for a mean of 16.2% of the area under the plasma concentration—time profile after intraarterial administration. Total systemic clearance, defined as the sum of elimination by all routes from the general circulation of the administered dose, and corrected for enterohepatic recirculation, averaged (±SD) 99.4 ±24.6 ml/min in the dog. An extended average apparent terminal half-life of 6.0±5.2hr was exhibited after oral administration compared to an average half-life of 3.1 ±1.8 hr following intraarterial administration. Elimination kinetics were linear in the dose range studied. Oral plasma concentration data suggest that the apparent bioavailable fraction may be dose dependent.     

Single-dose pharmacokinetics of felbamate in patients with renal dysfunction

Aims The purpose of this study was to evaluate the effects of renal impairment on the single-dose pharmacokinetics of the antiepileptic felbamate.
Methods Twelve subjects with three levels of renal dysfunction (creatinine clearance >30–80, >10–30 or 5–10  m  min⁻¹ ) and four controls with normal renal function (creatinine clearance >80  ml min⁻¹ were studied). Plasma and urine samples were obtained for 144  h following administration of a single 1200  mg dose.
Results Compared with controls, apparent total body clearance, renal clearance and urinary excretion of felbamate were decreased, and half-life, C _max and AUC values were increased in subjects with renal dysfunction. The magnitude of these changes was associated with the degree of renal dysfunction. Nonrenal clearance and apparent volume of distribution values were also lower in renal dysfunction subjects, but there was no association between the extent of these changes and degree of renal dysfunction. Renal clearance of felbamate accounted for approximately 30% of apparent total body clearance in the control group and from 9–22% in the renal failure patients. Renal clearance of felbamate was significantly correlated with creatinine clearance ( r ²=0.75; P <0.001).
Conclusions These data suggest that initial dosage and titration of felbamate may require adjustment in patients with renal dysfunction.     

The pharmacokinetics of midazolam in man

Summary Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1–2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25–0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37±0.45 h) did not differe significantly (t=2.04, df=10,p>0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74±0.45 h). The terminal half-life, (t_1/2), of midazolam in plasma was 1.77±0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383±0.094 l·kg^–1·h^–1. The first pass effect, F, determined experimentally (0.36±0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%–0.028%).     

Single-dose and multiple-dose pharmacokinetics of etintidine in healthy volunteers

Summary The present study was designed to determine the single- and multiple-dose pharmacokinetic profiles of the H₂ receptor antagonist etintidine in healthy volunteers.Etintidine was rapidly absorbed and eliminated after the oral administration of 300 mg base equivalent of etintidine HCl in a capsule formulation to 11 healthy subjects. Comparison of the pharmacokinetics after a single dose and during steady state showed no significant differences (p>0.05) in the mean values of C_max, t_max, oral clearance, elimination rate constant, and renal clearance, indicating no significant accumulation of etintidine and no apparent time-dependent changes in the pharmacokinetics of etintidine during multiple dose administration.     

HPLC法测定盐酸甲氧氯普胺注射液中甲氧氯普胺的含量

目的采用高效液相色谱测定盐酸甲氧氯普胺注射液的含量。方法采用C18（4.6 mm×250 mm,5μm）色谱柱;以甲醇-乙腈-醋酸盐缓冲液（pH=4,含0.1%三乙胺）（10∶15∶75）为流动相;流速：1.0 ml·min^-1;检测波长为273 nm;柱温：40℃;进样量：20μl。结果在该色谱条件下,甲氧氯普胺在17.00-170.00 mg·L^-1范围内呈良好的线性关系,r=0.999 9（n=8）,平均回收率99.9%（n=9）。结论所建立的方法灵敏、准确、简便,可作为盐酸甲氧氯普胺注射液的含量测定方法。     

甲氧氯普胺镇内脏痛的中枢多巴胺机制

在家兔内脏痛模型上观察了甲氧氯普胺(MCP)的镇痛作用。结果:MCP 8mg·kg~(-1)iv有明显的镇内脏痛作用.该作用可被多巴胺(DA)受体激动剂阿扑吗啡.D_1受体激动剂SKF38393.D_2受体激动剂LY171555 icv所拮抗。应用高效液相色谱—电化学检测法也观察到MCP8 mg·kg~(-1)iv20 min后.脑脊液中DA的代谢产物3-甲氧基-4-羟基苯乙酸明显升高。表明MCP的镇内脏痛作用与阻断脑内DA受体有关.D_1、D_2受体的激活均不利于MCP镇痛。     

HPLC法测定甲氧氯普胺片中甲氧氯普胺及有关物质的含量

目的建立测定甲氧氯普胺片中甲氧氯普胺及有关物质含量的方法。方法采用HPLC法。色谱柱为C18柱(250 mm×4.0 mm,5μm),流动相为乙腈-20 mmol.L-1磷酸溶液(体积比19∶81,用三乙胺调pH值至4.0),流速为1.0 mL.m in-1,检测波长为275 nm。结果在建立的色谱条件下,甲氧氯普胺与杂质能完全分离;甲氧氯普胺质量浓度在12.4~124 mg.L-1内与峰面积呈良好的线性关系,r=1.0000,平均回收率为100.5%(n=9);有关物质(按甲氧氯普胺计)的检出限为0.3ng。结论HPLC法可用于甲氧氯普胺片的质量控制。     

Pharmacokinetic characterization of the antiarrhythmic drug diprafenone in man

The pharmacokinetics of the antiarrhythmic drug diprafenone have been investigated in 6 healthy volunteers following single intravenous (50 mg) and oral doses (50 and 150 mg). Diprafenone was mainly eliminated by metabolism in the liver. Following i.v. infusion of 50 mg diprafenone, the terminal half-life of elimination was 1.50 h, the volume of distribution at steady-state was 1.23 l.kg-1, and the free fraction in plasma was 1.68%. Mean total plasma clearance was 741 ml.min-1.70 kg-1, which approaches normal liver blood flow after correction for the blood/plasma concentration ratio. Thus, diprafenone can be classified as a high extraction drug. Following oral administration, a dose-dependent increase in bioavailability from 10.9 (50 mg dose) to 32.5% (150 mg dose) was observed. The data suggest that diprafenone is subject to saturable hepatic first-pass metabolism.