Pharmacokinetics of propofol when given by intravenous infusion.

We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half-life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h-1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half-life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4-5 half-lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half-life of the drug. Therefore, the long elimination half-life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.     

Extended blood collection period required to define distribution and elimination kinetics of propofol.

The pharmacokinetics of propofol were investigated following bolus intravenous administration of 2-3 mg kg-1 of drug to eight surgical patients. Apparent elimination half-life, volume of distribution and systemic blood clearance of propofol correlated strongly with the sampling period, which ranged from 8 to 52 h, depending on the time taken for the propofol concentration to reach the detection limit of the assay. In the three patients in whom the sampling period exceeded 42 h, apparent elimination half-life (55.6 h) and apparent volume of distribution (1370 l) greatly exceeded previously published estimates and systemic blood clearance (1020 ml min-1) was much less than previous estimates. This suggests that previous estimates were biased by the relatively short duration of blood collection in those studies (8 to 12 h).     

Pharmacokinetics of sulphadimethoxine in channel catfish (Ictalurus punctatus)

1. Plasma clearance, bioavailability, tissue disposition and elimination of 14C-sulphadimethoxine (SDM) were studied in channel catfish (Ictalurus punctatus) after intravenous (i.v.) and oral dosing (per os; p.o.) at 40 mg/kg body weight. 2. Analysis of blood SDM concentrations over time for intravascularly administered SDM showed that disposition and elimination were best described by a two-compartment pharmacokinetic model; estimated half-lives for SDM in blood were 0.09 and 12.6 h for the distribution and elimination phases, respectively. 3. SDM was found primarily in muscle tissue immediately after oral administration; however, clearance from muscle was rapid, with a half-life of 13.1 h. 4. With time, SDM-derived radioactivity became concentrated in the bile and was eliminated slowly (t 1/2 = 115.5 h). 5. Binding of SDM in channel catfish plasma was low (18%) and was non-specific and dose-independent. 6. With the exception of the initial, rapid clearance of SDM from blood, the pharmacokinetic parameters describing SDM distribution and elimination in channel catfish were similar to values reported for other vertebrate species; the rapid distribution of SDM from blood to the tissues in the catfish may be related to species differences in the plasma binding of SDM.     

High-dose morphine and methadone in cancer patients. Clinical pharmacokinetic considerations of oral treatment

Several clinical studies have shown oral morphine and methadone to be effective in the treatment of intractable pain in patients with malignant disease. Recent pharmacokinetic studies have confirmed the rationale for regular administration of oral morphine and methadone but have revealed marked interindividual differences in the kinetics and metabolism which must be considered when titrating the oral dose according to the individual patient's need. Oral absorption of morphine in patients with malignant diseases is rapid, with peak plasma concentrations occurring at 20 to 90 minutes. Predose steady-state concentrations bear a constant relationship to dose, but vary considerably between individuals. The oral bioavailability is approximately 40% with marked patient-to-patient variations as a result of differences in presystemic elimination. The reported values for the volume of distribution range from 1.0 to 4.7 L/kg. Plasma protein binding is about 30%. The elimination half-life varies between 0.7 and 7.8 hours. Plasma clearance is approximately 19 ml/min/kg (5 to 34 ml/min/kg) and mostly accounted for by metabolic clearance. Studies in a few patients with malignant diseases treated regularly with daily doses of oral morphine ranging from 20 to 750mg indicate a linear relationship between the dose and trough concentration of morphine. Long term treatment with 10- to 20-fold increase of the oral dose over a period of 6 to 8 months does not seem to change the kinetics of oral morphine. The plasma concentrations of the main metabolite, morphine-3-glucuronide (M3G), exceed those of the parent drug by approximately 10-fold after intravenous administration and by 20-fold after oral administration. The relationship between the area under the plasma concentration-time curve (AUC) of morphine and the AUC of morphine-3-glucuronide remains constant during the development of tolerance upon long term treatment with increasing doses. Renal disease causes a significant increase in the mean plasma concentrations of morphine for 15 minutes after its administration, while mean values of terminal half-life and total body clearance are within the normal range. However, the glucuronidated polar metabolite morphine-3-glucuronide rises rapidly to high concentrations which persist for several days. Chronic liver disease causes an increase in the bioavailability of oral morphine but no, or only a slight reduction in the intravenous clearance. The elimination half-life and volume of distribution are within the normal range.(ABSTRACT TRUNCATED AT 400 WORDS)     

Metoclopramide pharmacokinetics in pregnant and nonpregnant sheep

The pharmacokinetics of metoclopramide was studied in chronically instrumented pregnant and nonpregnant sheep. Metoclopramide was administered to the ewe by intravenous bolus injections (on a crossover basis) of 10, 20, and 40 mg, with an additional 80-mg dose to the nonpregnant animals. Transfer of the drug to the fetus was rapid with significant concentrations in fetal plasma 1 min after maternal dosing. The ratio of fetal-to-maternal area under the plasma concentration-time curves averaged 0.74, indicating significant fetal exposure to the drug. Maternal metoclopramide administration resulted in minimal fetal effects, with no change in arterial pressure, heart rate, or arterial pH or PCO2, and only a small (approximately 1.8 mmHg) transient decline in PO2. Plasma concentrations in maternal and fetal plasma in most animals were best described by a biexponential equation with rapid distribution and elimination phases. The terminal elimination half-lives in maternal and fetal plasma averaged 71.3 and 86.8 min, respectively, with fetal half-life being significantly longer. The number of fetuses present had no consistent effects on either maternal or fetal pharmacokinetic parameters. Total body clearance and volume of distribution averaged 3.5 L/h/kg and 5.8 L/kg, respectively, in the pregnant ewe, and 4.5 L/h/kg and 6.9 L/kg, respectively, in the nonpregnant animals. The terminal elimination half-life in the nonpregnant ewes averaged 67.5 min. Pharmacokinetic parameters were compared in the pregnant and nonpregnant ewes at the 10-, 20-, and 40-mg doses, and no significant differences were observed in the distribution or elimination rate constants, elimination half-life, or volume of distribution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Long-Term Drugs on Alfentanil Clearance in Patients Undergoing Renal Transplantation

Although patients in renal failure frequently take several drugs on a long-term basis, drug-induced alterations in alfentanil metabolism have not been examined as a possible source of variability in alfentanil clearance in this population. We compared the pharmacokinetics of alfentanil during renal transplantation in seven patients receiving and six not receiving long-term drug therapy. After the rapid intravenous injection of alfentanil 100 μg/kg during isoflurane anesthesia, plasma concentrations were measured at intervals up to 6 hours by radioimmunoassay. The terminal elimination half-life, steady-state volume of distribution (Vd_ss), and total body clearance were determined by non-compartmental methods. There was no statistical difference in the Vd_ss between the two patient groups. However, clearance was significantly higher and elimination half-life lower in the group taking long-term drugs: clearance 6.94 ± 4.64 versus 3.47 ± 0.16 ml·kg⁻¹·min⁻¹, and elimination half-life 50.6 ± 13.9 versus 90.7 ± 22.4 minutes, respectively (p<0.05). The higher clearance occurred even though five of the seven patients were taking agents known to be metabolized by the same cytochrome P-450 hepatic isozyme that metabolizes alfentanil and therefore potential competitive inhibitors of alfentanil metabolism. Drugs taken by the three patients with the highest alfentanil clearances included known inducers of hepatic drug metabolism. Thus, in the presence of several long-term drugs, the clearance of alfentanil appears to be noticeably increased by inducers of hepatic drug metabolism but unaffected by potential competitive inhibitors.     

盐酸阿芬太尼在手术病人中的药代动力学研究

本文进行了两组不同剂量的阿芬太尼在14例手术病人中药代动力学研究。7例一次性iv 80μg·kg~(-1)阿芬太尼,另7例一次性iv 40μg·kg~(-1)。用RIA方法测定0-8 h阿芬太尼的血浆浓度和0-48 h尿中的回收率。研究表明:阿芬太尼在两组病人体内的药代动力学过程均为3室模型。阿芬太尼的初级消除很快,给药后30 min内90％的原型药被消除。病人血浆浓度未发现2次上升现象。二者药-时曲线接近平行,说明阿芬太尼的代谢过程为1级消除。两组阿芬太尼的药代动力学数据经t检验无显著差异(P>0.05)。阿芬太尼的快、慢分布相和消除相的半衰期t_(1/2)π,t_(1/2)α和t_(1/2)β分别为0.71 min±s 0.37 min,11.66 min±s 3.46 min和86.12 min±s 19.15 min;平均总体和中心室的分布容积Vd、Vc分别为34.22L±s 8.27L和4.23L±s 1.72L;平均总体清除率Cl为0.29 L·min~(-1)±s 0.08L·min~(-1)。另外,k_(12)/k_(21)为1.5,k_(13)/k_(31)为3.5,k_(10)大于k_(31)。用药后48 h以内,40μg·kg~(-1)组和80μg·kg~(-1)组的病人尿中排出的原形阿芬太尼分别占总给药量的0.68％±s 0.72％和0.66％±s 0.54％。其肾清除率分别为0.0016 L·min~(-1)±s 0.0011 L·min~(-1)和0.0021 L·min~(-1)±s 0.0015 L·min~(-1)。     

Pharmacokinetics of sulphadimethoxine in channel catfish (Ictalurus punctatus)

1. Plasma clearance, bioavailability, tissue disposition and elimination of ¹⁴C-sulphadimethoxine (SDM) were studied in channel catfish (Ictalurus punctatus) after intravenous (i.v.) and oral dosing (per os; p.o.) at 40 mg/kg body weight.

2. Analysis of blood SDM concentrations over time for intravascularly administered SDM showed that disposition and elimination were best described by a two-compartment pharmacokinetic model; estimated half-lives for SDM in blood were 0.09 and 12.6 h for the distribution and elimination phases, respectively.

3. SDM was found primarily in muscle tissue immediately after oral administration; however, clearance from muscle was rapid, with a half-life of 13.1 h.

4. With time, SDM-derived radioactivity became concentrated in the bile and was eliminated slowly (t_1/2 = 115.5h).

5. Binding of SDM in channel catfish plasma was low (18%) and was non-specific and dose-independent.

6. With the exception of the initial, rapid clearance of SDM from blood, the pharmacokinetic parameters describing SDM distribution and elimination in channel catfish were similar to values reported for other vertebrate species; the rapid distribution of SDM from blood to the tissues in the catfish may be related to species differences in the plasma binding of SDM.     

Pharmacokinetics of intravenous amikacin after rapid and slow infusion with special reference to hemodialysis.

The pharmacokinetics of amikacin, a recently introduced aminoglycoside structurally related to kanamycin, were determined in healthy volunteers after rapid and slow constant-rate intravenous administration of a 7.5 mg/kg dose. The elimination profile of amikacin can be described by two compartment open model kinetics. Peripheral distribution of the drug is extremely rapid, and beta-phase concentrations decay with a half-life averaging about 2 hours, while inter-compartmental equilibrium is achieved in a little over 30 minutes. The volume of distribution averages about 25% of body weight. During hemodialysis, amikacin extraction from the blood reaches 97% +/- 17% (mean +/- 95% confidence interval) that of creatinine and 89% +/- 20% that of blood urea nitrogen. A method of administration adapted to the kinetic properties of the antibiotic is proposed.     

Clinical pharmacokinetics of the newer neuromuscular blocking drugs

The pharmacokinetics of 6 new neuromuscular blocking drugs are described. These are the aminosteroids pipecuronium bromide, rocuronium bromide and rapacuronium bromide (ORG-9487) and the benzylisoquinolinium diesters doxacurium chloride, mivacurium chloride and cisatracurium besilate. In healthy individuals, these drugs all have similar volumes of distribution. Their pharmacokinetics are influenced little by age or anaesthetic technique, but renal and hepatic disease may significantly alter their distribution and elimination. Pipecuronium resembles pancuronium in its pharmacokinetic and neuromuscular blocking profile, but is devoid of cardiovascular effects. It has a low clearance (0.16 L/h/kg) and long elimination half-life (120 minutes). It is largely eliminated through the kidney. Rocuronium has a similar pharmacokinetic profile to vecuronium but its onset of action is more rapid and duration of action slightly shorter. Its clearance (0.27 L/h/kg) is intermediate between those of pipecuronium and rapacuronium, but its elimination half-life is long (83 minutes). The pharmacokinetics of rocuronium are altered by renal and hepatic disease; the latter probably has the more significant effect. Rapacuronium has a rapid onset, and a bolus dose has a short duration of action. It has a high clearance (0.59 L/h/kg) but a long elimination half-life (112 minutes). Doxacurium has a pharmacokinetic and pharmacodynamic profile similar to pipecuronium. It has a high potency and is devoid of cardiovascular effects. In adults, it has a low clearance (0.15 L/h/kg) and long elimination half-life (87 minutes). Mivacurium is a mixture of 3 stereoisomers. It has a short to intermediate duration of action. It is hydrolysed by plasma cholinesterase. Inherited or acquired alterations in plasma cholinesterase activity are associated with changes in the pharmacokinetics and time course of action of mivacurium. The 2 active isomers (cis-trans and trans-trans) have a high clearance (4.74 L/h/kg) and very short elimination half-lives (approximately 2 minutes). Cisatracurium is the 1R-cis 1'R-cis isomer of atracurium. It has similar pharmacokinetics and pharmacodynamics to atracurium. It is mainly broken down by Hofmann (non-enzymatic) degradation. Cisatracurium has an intermediate clearance (0.3 L/h/kg) and short elimination half-life (26 minutes). Hepatic and renal disease have little effect on its pharmacokinetics.     

Clinical pharmacokinetics of the newer intravenous anaesthetic agents

In the last 15 years the role of opioids in anaesthesia management has undergone dramatic change. Initially used as premedicants, or adjuvants to inhalation anaesthetic agents or as analgesics for postoperative pain relief, narcotics have now evolved into primary anaesthetic agents, primarily because of their ability to maintain cardiovascular stability especially in patients with compromised myocardial function. Sufentanil, alfentanil, and lofentanil are 3 new synthetic congeners of fentanyl. Sufentanil and alfentanil afford not only the haemodynamic stability but also the desirable anaesthetic properties of analgesia, and unconsciousness. Their major advantage lies in their pharmacokinetic behaviour; a rapid onset of action and short elimination half-life, allowing for greater flexibility in anaesthetic management. Sufentanil's pharmacokinetic profile is consistent with a 2-compartment model. Its elimination half-life is 149 minutes and its clearance is 11.3 ml/min/kg. Alfentanil's pharmacokinetic profile has been described by both 2- and 3-compartment models. Its distribution and redistribution are rapid, with an elimination half-life of 83 to 137 minutes and a clearance of 4.37 to 6.47 ml/min/kg in adult patients. Lofentanil, however, is an extremely long-acting narcotic analgesic. Presently, its use is justified only when prolonged mechanical ventilation is anticipated. Etomidate, a carboxylated imidazole, is rapidly distributed within a central compartment and then to peripheral compartments; its slow distribution and terminal elimination half-lives are 28 and 273 to 330 minutes, respectively, and its clearance (11.6 to 25 ml/min/kg) is equal to its hepatic plasma flow. Its ability to maintain cardiovascular stability in patients with compromised myocardial function make it a useful induction agent. However, reports of increased mortality and inhibition of steroidogenesis in patients receiving either single injections or constant infusions have created controversies regarding its use. Minaxolone is a water-soluble steroid whose pharmacokinetic profile is consistent with a 2-compartment model. Distribution is rapid with a mean half-life of 2.1 minutes and an elimination half-life of 47 minutes. There do not appear to be any cumulative effects. Plasma levels on recovery were similar in those patients receiving single bolus or continuous infusions. Midazolam and flunitrazepam are two new benzodiazepines. As a class of drugs, benzodiazepines provide the pharmacological properties of anxiolysis, sedation, hypnosis, muscle relaxation, amnesia and anticonvulsant activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics of leucovorin calcium after intravenous, intramuscular, and oral administration

The pharmacokinetics of leucovorin was evaluated after intravenous, intramuscular, and oral administration in a randomized crossover study of 37 healthy men. A single 25-mg dose of leucovorin calcium was administered intravenously, intramuscularly, or orally to the subjects. Blood samples were obtained immediately before and at 13 time points up to 24 hours after the leucovorin dose. The three treatment phases were separated by one-week intervals. Bioavailability was assessed by measuring over 24 hours the blood concentrations of total folates, the parent compound 5-formyltetrahydrofolate, and the metabolite 5-methyltetrahydrofolate, using differential microbiologic assays with Lactobacillus casei and Streptococcus faecalis. Both intravenous and intramuscular administration produced rapid increases in serum concentrations of biologically active folates; these rises were sustained over time and were still detectable at 24 hours after drug administration. The bioavailability of intravenous and intramuscular doses was comparable based on area under the serum concentration-time curve, although for intramuscular administration, the peak concentration was lower and the time to peak concentration was longer. The initial rise in serum folate with intravenous and intramuscular dosing represented 5-formyltetrahydrofolate; this fell concomitantly with the appearance of 5-methyltetrahydrofolate. Oral leucovorin was 92% bioavailable compared with intravenous administration and produced a predictably different pattern of circulating folates, 5-methyltetrahydrofolate being the predominant form. Terminal elimination half-life, apparent volume of distribution, and clearance of total folate were not significantly different among the three treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and clinical use of flumazenil (Ro 15-1788)

Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist which can prevent or abolish selectively at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration flumazenil is rapidly absorbed (peak concentrations are achieved after 20 to 90 minutes), but bioavailability is low (16%) due to significant presystemic elimination. As less than 0.2% of an intravenous dose was recovered as unchanged drug in the urine, extensive metabolism must occur and so far 3 metabolites of flumazenil (N-demethylated and/or hydrolysed products) have been identified. For the clinical value of flumazenil a rapid onset of action is mandatory, which is facilitated by its fast uptake and regional brain distribution as verified by positron emission tomography. The limited duration of benzodiazepine-antagonistic action of flumazenil (2 to 3 hours) is due to its rapid hepatic elimination. This can be characterised either by the short half-life (0.7 to 1.3 hours) or better by the high plasma or blood clearance of 520 to 1300 ml/min (31 to 78 L/h). The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6 to 1.6 L/kg) or its partly flow-dependent hepatic elimination. Whereas in first trials flumazenil appeared to be without its own pharmacological effects, there is now increasing evidence that flumazenil is not devoid of intrinsic actions. Dependent on the dose, the basal clinical conditions and experimental tests, flumazenil has both weak agonist-like and inverse agonist-like properties which might be explained by a modulation of GABA-ergic activity. In several clinical studies intravenous doses down to 0.2mg of flumazenil initiated a rapid and reliable reversal of benzodiazepine-induced sedation, hypnosis or coma. Small incremental intravenous doses of 0.1 to 0.2mg of flumazenil are useful in benzodiazepine intoxications, in differential diagnosis of coma, excessive postoperative sedation and possibly in reversing paradoxical reactions of benzodiazepines. Because flumazenil is short acting, careful clinical observation is crucial. To maintain its antagonistic action repeated administrations will be necessary. At present, the therapeutic indications are restricted to some special situations. However, flumazenil is an interesting agent, which might contribute also to a better understanding and future development of more specific benzodiazepines, hopefully without the potential for dependence seen with existing compounds.     

Propofol in cesarean section. A pharmacokinetic and pharmacodynamic study

The induction properties and pharmacokinetics of propofol, 2.5 mg/kg i.v., were studied in twelve unpremedicated healthy pregnant patients at term. The onset of anesthesia was rapid (27.7 +/- 7.3 sec) and the quality of induction, maintenance of and rapid recovery from anesthesia were clinically very acceptable. On the basis of Apgar scores and blood gas analyses of the feto-placental unit, propofol appears to be a safe alternative to other available induction agents. The pharmacokinetics of propofol in pregnant women (n = 8) were described by a high value for total body clearance (mean 2189.6 ml/min) and a short elimination half-life (mean 24.1 min). There was no correlation between the pharmacokinetic parameters determined for propofol and some pharmacodynamic observations during the induction of anesthesia (n = 8), nor was there any correlation between drug levels of propofol in the feto-placental unit and blood-gas tensions and pH values or Apgar scores (n = 12).     

Propofol: a review of its use in intensive care sedation of adults

Propofol (Diprivan) is a phenolic derivative with sedative and hypnotic properties but is unrelated to other sedative/hypnotic agents. Formulated as an oil-in-water emulsion for intravenous use, it is highly lipophilic and rapidly crosses the blood-brain barrier resulting in a rapid onset of action. Emergence from sedation is also rapid because of a fast redistribution into peripheral tissues and metabolic clearance. The depth of sedation increases in a dose-dependent manner. In well designed clinical trials in patients receiving sedation in the intensive care unit (ICU) for a variety of indications, propofol provided adequate sedation for a similar proportion of time to midazolam, but the rate of recovery was faster with propofol. Even after periods of prolonged sedation (>72 hours), propofol was generally associated with a faster time to recovery than midazolam. Propofol facilitated better predictability of recovery and an improved control of the depth of sedation in response to titration than midazolam. In patients sedated following head trauma, propofol reduced or maintained intracranial pressure. Propofol is associated with generally good haemodynamic stability but induces a dose-dependent decrease in blood pressure and heart rate. Bolus administration may cause transient hypotension, and slow initial infusions are recommended in most patients. Serum triglyceride concentrations should be monitored during prolonged infusions (>3 days) because of the risk of hypertriglyceridaemia. The administration of 2% propofol can reduce this risk. Strict aseptic technique must be used during the handling of the product to prevent accidental extrinsic microbial contamination. Despite a higher acquisition cost with propofol, most studies of short-term sedation (approximately <3 days) showed that overall costs were lower with propofol than with midazolam, because a faster time to extubation reduced total ICU costs. However, as the period of sedation increased, the cost difference decreased. CONCLUSION: The efficacy of propofol in the sedation of adults in the ICU is well established, and clinical trials have demonstrated a similar quality of sedation to midazolam. Because of a rapid distribution and clearance, the duration of action of propofol is short and recovery is rapid. Emergence from sedation is more rapid with propofol than with midazolam, even after long-term administration (>72 hours), which enables better control of the depth of sedation in response to titration and more predictable recovery times. Thus, for the ICU sedation of adults in a variety of clinical settings, propofol provides effective sedation with a more rapid and predictable emergence time than midazolam.     

Comparative pharmacokinetics of propofol in Chinese adults and children.

The pharmacokinetics of propofol were studied in 14 healthy young male Chinese adults, aged 18-38 years, undergoing minor orthopedic surgery. All patients who received a single bolus dose of propofol 2.5 mg/kg were paralyzed with atracurium and mechanically ventilated. Anesthesia was maintained with 67% nitrous oxide plus 1-2% isoflurane in oxygen with alfentanil 5 micrograms/kg intravenously as a bolus injection. Blood concentrations of propofol over the subsequent 24 hours were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistently described by a three compartment model but analysis revealed two significantly different blood propofol concentration-time profiles (p less than 0.05). Five patients, designated "fast" metabolizers, demonstrated a mean elimination half-life which was shorter than that described in Chinese children, while their total body clearance was similar. Nine other patients, designated "slow" metabolizers, had a longer mean elimination half-life and slower total body clearance than those in elderly Caucasian patients. This may be suggestive of propofol metabolism at some extra-hepatic site in some patients, while other patients demonstrate marked lipophilicitic constraint of the drug by the deep compartment.     

Pharmacokinetics of amiodarone in rats

We studied the kinetics of amiodarone in the rat. After an intravenous dose of 50 mg/kg, the time-course of the drug concentrations was assessed by high-pressure liquid chromatography in blood and tissues up to 16 h. The drug disappeared from the blood with an elimination half-life (t1/2beta) of 514 min and distributed extensively into tissues [apparent volume of distribution (Vd)= 29.51 L/kg]. Concentrations were highest in liver, kidney, and heart, and lowest at all times in the brain. The highest concentrations were found within 5-30 min of administration.Amiodarone accumulated extensively in adipose tissue and reached a fat/blood concentration ratio of about 1,000 at 16 h. Single-pass rat liver perfusion experiments gave an hepatic extraction ratio of 0.49 and an intrinsic clearance of 5.48 ml/min. Amiodarone disappearance in rat liver recirculation experiments was biexponential, with a half-life of 58 min.     

Clinical pharmacokinetics of bretylium

Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of probenecid on the delivery of morphine-6-glucuronide to the brain.

The objective was to evaluate the influence of probenecid on the blood-brain barrier (BBB) transport of morphine-6-glucuronide (M6G). Microdialysis probes were placed in the striatum and into the jugular vein of Sprague-Dawley rats. Each probe was calibrated in vivo using retrodialysis by drug. M6G was administered as a 4-h exponential i.v. infusion, and the experiment was repeated the following day with the addition of probenecid. The data were analysed using NONMEM. An integrated model including the total arterial concentrations, the dialysate concentrations in brain and blood, and the recovery measurements, was developed. The extent of BBB transport, expressed as the ratio between clearance into the brain and clearance out of the brain (CL(in)/CL(out)), was estimated as 0.29 on both days, indicating that efflux transporters act on M6G at the BBB. However, the probenecid-sensitive transporters are not involved in the brain efflux, as the ratio was unaltered although probenecid was co-administered. In contrast, the systemic elimination of M6G decreased by 22% (p<0.05) upon probenecid co-administration. The half-life of M6G was longer in the brain than in blood on both experimental days (p<0.05). In conclusion, probenecid decreased the systemic elimination of M6G, but had no effect on the BBB transport of M6G.     

Nonlinear pharmacokinetic characteristics of 5-fluorouracil (5-FU) in colorectal cancer patients

Summary The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma.A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination.The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.