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Pharmacokinetics and pharmacodynamics ofcinacalcet in patients with renal failure receiving hemodialysis and hemodiafiltrationtherapy .

Few studies have focused on the effects of dialysis on cinacalcet. In addition, there is no data available on hemodiafiltration (HDF) all over the world. Therefore, we studied the pharmacokinetics (PK) and pharmacodynamics (PD) of cinacalcet in patients undergoing hemodialysis (HD) or HDF to provide more guiding information on its use in these patients, especially in China. In this open-label, single-dose, single-center study of 7 patients with renal failure who underwent dialysis, patients were randomly allocated to two groups consisting of 4 and 3 patients who received low-flux HD and HDF treatments, respectively. All participants underwent dialysis for 4 hours immediately after receiving single oral doses of a 25mg cinacalcet tablet. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and electrochemical luminescence (EI) were used to determine the cinacalcet plasma concentrations and intact parathyroid hormone (iPTH) serum levels, respectively. Peak concentration (Cmax) and area under the curve (AUC) from time 0 to 24 hours (AUC0-24h) of the low-flux HD therapy group were 21.8±18.6 ng/mL and 145.3±91.8 ng×h/mL, respectively, which were similar to those of the HDF group (30.9±7.9 ng/mL and 161.6±26.5 ng×h/mL, respectively). iPTH concentrations of the HD therapy group decreased after cinacalcet administration and increased following its clearance. However, iPTH levels of subjects receiving HDF therapy did not change. Compared with healthy Chinese subjects, patients with renal failure had a higher Cmax and AUC0-24h, slightly prolonged time to Cmax (tmax) after administration of the same dose of cinacalcet. On HD treatment day, variation trends of iPTH in Chinese patients and healthy subjects were similar and significantly different from that on the HDF treatment day. Considering the high protein binding rate of cinacalcet, this may lead to the great free-drug clearance during HDF treatment.

Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)

We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.

Pharmacokinetics of Vilazodone in Patients with Mild or Moderate Renal Impairment

In patients with impaired renal function, the pharmacokinetics of a drug may be altered, resulting in decreased renal excretion or metabolism, and altered absorption, plasma protein binding or distribution. Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder. Vilazodone is extensively hepatically metabolized with minimal renal excretion. The primary objective of this study was to assess the pharmacokinetics of a single 20-mg dose of vilazodone in subjects with mild or moderate renal impairment. This was a Phase 1, open-label, single-dose study of vilazodone in community-dwelling subjects with renal impairment and in healthy subjects to evaluate the pharmacokinetics of vilazodone in the presence of renal impairment. Thirty-two subjects were enrolled: eight subjects with mild (estimated glomerular filtration rate [est GFR] >50-80mL/min) renal impairment matched individually by age, sex and body mass index to eight control subjects with normal renal function (est GFR >80mL/min), and eight subjects with moderate (est GFR≥30-50mL/min) renal impairment matched with eight control subjects with normal renal function. Subjects received a single, 20-mg dose of vilazodone and pharmacokinetics, safety and plasma protein binding were assessed for 14days. The pharmacokinetic parameters calculated were maximum plasma concentration (Cmax), time to maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time zero to 24h, AUC from time zero to the last measurable concentration, AUC from time zero to infinity estimated by linear trapezoidal rule and extrapolation, oral clearance, terminal elimination rate constant, elimination half-life (t½), free fraction in plasma, apparent free drug clearance, amount of vilazodone recovered in urine 0-96h following drug administration, percent of dose recovered in urine over 96h following drug administration, renal clearance and volume of distribution. Safety assessments were adverse events, clinical laboratory test results, 12-lead electrocardiograms and vital signs. Vilazodone pharmacokinetic parameters in renally impaired subjects were variable but not substantially different from healthy controls. Mean values for vilazodone Cmax and AUC were similar among groups. Mean t½ (35.7 and 34.8h mild and moderate vs. 37.0 and 34.8h matched controls), total drug clearance (19.9 and 25.1L/h vs. 26.4 and 26.9L/h), and mean vilazodone recovery in urine (1.21% and 0.58% vs. 0.95% and 0.81%) were similar for mild and moderate renally impaired subjects and matched controls with normal renal function. There were no apparent systematic trends in vilazodone pharmacokinetic parameters associated with decreasing renal function. Protein binding was variable (coefficient of variation, 29-65 %) but not substantially different among the three groups, and total drug clearance was not affected. Safety and tolerability of vilazodone were comparable in all groups of subjects. This study suggests that systemic exposure of vilazodone is not affected by mild or moderate renal impairment. No dose adjustments are recommended in patients with mild or moderate renal impairment.

Increased unbound drug fraction in acute carbamazepine intoxication: suitability and effectiveness of high-flux haemodialysis

Dear Editor, A 61-year-old woman (patient A) was admitted to our intensive care unit with carbamazepine overdose. Carbamazepine total plasma concentration determined by enzyme-multiplied immunoassay technique (EMIT) was 52.5 mg/L (reference 4–12 mg/L) of which 22.7 mg/L was unbound (43%). Unbound carbamazepine was determined in plasma by EMIT after ultrafiltration (Amicon Ultra centrifugal filter (Millipore), 2,500 rpm, 30 min at 25°C). Despite supportive care (pacemaker, inotropes and vasopressors) and multiple activated charcoal administration, the patient died shortly after admission as a result of refractory shock. Soon after, a 41-year-old man (patient B) was admitted after resuscitation due to ventricular fibrillation. For epilepsy he was treated with carbamazepine (400 mg 5 times/day). As a result of repeated ventricular fibrillation, intravenous amiodarone (300 mg/day) was started. Two days later a deep coma developed. Because of a high daily dose of carbamazepine and its interaction with amiodarone, we suspected a carbamazepine intoxication. Total carbamazepine plasma concentration was 27.4 mg/L of which 10.9 mg/L was unbound (40%). Carbamazepine intoxication was treated with multiple-dose activated charcoal and high-flux haemodialysis (HF-HD); filter Fresenius Helixon® FX1000, blood flow 350 mL/min, dialysate flow 500 mL/min, ultrafiltration rate 120 mL/h, ultrafiltration coefficient 75 mL/(h mmHg). Carbamazepine plasma concentration decreased to 13.0 mg/L (4.1 mg/L unbound; 32%) (Fig. 1). The patient fully recovered. Fig. 1 Carbamazepine total (solid circles) and unbound (open circles) plasma concentrations in patient B. Therapeutic range for total plasma concentrations 4–12 mg/L Treatment of carbamazepine intoxication consists of supportive care, prevention of further absorption and enhancement of elimination via haemoperfusion [1, 2]. But haemoperfusion has serious adverse effects and the facilities are often not available [1, 3]. Effectiveness of haemodialysis depends on drug characteristics, dialysis system properties and dialysis conditions. Haemodialysis in carbamazepine overdose is considered not to be efficacious because of low hydrophilicity (Log P = 1.98) and the high degree of protein binding (70–80%), although carbamazepine is small enough for filtration (236 Da) and has a low distribution volume (0.8–1.8 L/kg) [1]. Elimination rate constants (k), calculated as k = ln 2/half-life (h), reflect the effectiveness of the elimination route. Overall k is defined as the sum of all individual k values. Calculated individual k values in patient B were 0.009/h for endogenous metabolism, 0.059/h for dialysis (including membrane adsorption) and 0.039/h for charcoal treatment. Endogenous k was calculated from the time period in which no activated charcoal or HF-HD was applied. k of activated charcoal was calculated by subtracting k endogenous from k overall when only endogenous clearance and activated charcoal therapy were present. k dialysis is k overall during HF-HD minus k endogenous and k activated charcoal. Limited blood sampling during the initial rapid clearance of free drug from the plasma by HF-HD may partly hamper the interpretation of the results. However, on the basis of the half-life initially and later on during HF-HD, we assume that no significant rapid initial phase took place (see Fig. 1). HF-HD was more effective than multiple activated charcoal treatment alone, whereas the combination of both was about ten times more effective than endogenous clearance. Probably, endogenous k was decreased because of the presence of amiodarone, a CYP3A4 inhibitor [4]. Owing to the increased unbound drug concentration in carbamazepine intoxication, HF-HD proved to be an effective extracorporeal elimination technique. In conclusion, HF-HD is an effective extracorporeal elimination technique in carbamazepine intoxication as a result of the increased unbound drug fraction and can replace haemoperfusion.

Free Drug Metabolic Clearance in Elderly People

The question of whether metabolic drug clearance is decreased in elderly people has been the subject of considerable debate and is very important because clearance is a determinant of dosing. Drug clearance has been shown to be consistently impaired for flow-limited (high-clearance) drugs, but there have been conflicting results for capacity-limited (low-clearance) drugs. A limitation of the studies of capacity-limited drugs is that most have estimated clearance based on total drug concentrations (protein-bound plus free). Total drug clearance reflects both the intrinsic clearance of free drug and the extent of protein binding. Total clearance is a valid measure for capacity-limited drugs with low protein binding and appears to be consistently impaired in elderly subjects. For phenazone [antipyrine] (fraction unbound [f(u)] >0.9), seven studies have demonstrated statistical reductions in clearance of 20-52%. For theophylline (f(u) 0.6), five studies have demonstrated reductions in clearance of 22-35%. For paracetamol [acetaminophen] (f(u) 0.8), the clearance of which has been quoted as unchanged, four studies have demonstrated reductions in clearance of 19-35%. For highly protein-bound drugs, total clearance is not the appropriate parameter. Free drug clearance is more appropriate since it is independent of changes in protein binding. The literature was reviewed to test the hypothesis that in elderly people, capacity-limited drugs with high protein binding will show decreased free clearance even in the absence of a decrease in total clearance. For these drugs, data for free drug clearance based on measurement of actual free drug concentrations are limited, but suggest that the intrinsic metabolic clearance is impaired in elderly subjects. Four studies of naproxen (f(u) <0.01) have shown reduced free drug clearance of 50% or more. Two studies of valproic acid (f(u) 0.1-0.2) have shown reduced free clearance of 39% and 65%. Two studies of ibuprofen (f(u) <0.01) have shown reduced free clearance of S-ibuprofen of 21% and 28%. There is some indirect evidence for reduced clearance of the highly protein-bound drugs oxaprozin, temazepam, lorazepam, diazepam, phenytoin and warfarin, although studies measuring free concentrations are lacking. Together, the above studies support the hypothesis that the intrinsic metabolic drug clearance is impaired in elderly subjects, in the order of 20-60%, and that this effect is masked if highly protein-bound drugs are assessed using total drug clearance. If the findings are confirmed in future well-designed studies of free drug clearance, there are profound and beneficial implications for dosing of drugs in elderly people. Lower doses are likely to achieve appropriate concentrations, allowing full efficacy but decreased dose-related adverse effects.

Quinine pharmacokinetics in chronic haemodialysis patients.

Quinine is often used to prevent muscle cramps in patients with chronic renal failure. A standard dose of 300 mg at bedtime is usually recommended, but little is known about the pharmacokinetics of quinine in the presence of renal failure. We studied the pharmacokinetics of quinine in eight normal subjects and eight patients with chronic renal failure on haemodialysis after a single oral dose of quinine sulphate (300 mg). The concentration of alpha1-acid glycoprotein (AAG), the major binding protein for quinine, was increased in haemodialysis patients compared with control subjects (1.52 g l-1 vs 0.63 g l-1 [mean difference 1.033; 95% CI 0.735, 1.330]) whereas albumin levels were decreased (30 g l-1 vs 40 g l-1 [mean difference 9.5; 95% CI 3.048, 15.952]). Accordingly, the free fraction of quinine was decreased (0.024 vs 0.063 [mean difference 0.0380; 95% CI 0.0221, 0.0539]) and the apparent volume of distribution tended to decrease (0.95 l kg-1 vs 1.43 l kg-1 [mean difference 0.480; 95% CI 0.193, 1.154]). The quinine binding ratio correlated with the plasma concentration of AAG but not that of albumin. The clearance of free (unbound) quinine was increased in haemodialysis patients compared with controls (67.9 ml min-1 kg-1 vs 41.1 ml min-1 kg-1 [mean difference -26.8; 95% CI, -56.994, 3.469]), and the area under the curve (AUC) of the two main metabolites, 3-hydroxyquinine and 10,11-dihydroxydihydroquinine were increased. In patients with chronic renal failure, there is an increase in plasma protein binding and in the clearance of free drug, resulting in lower plasma concentration of free quinine.

Pharmacokinetic and pharmacodynamic principles of illicit drug use and treatment of illicit drug users.

Many clinicians are confronted by the use of illicit drugs on a daily basis. The unsanctioned use of opioids, psychostimulants, benzodiazepines, alcohol and nicotine is a major cause of morbidity and mortality. Multiple factors have inhibited the scientific study of these agents including prohibition, public denial and lack of commercial interests. In dealing with problems related to these drugs, clinicians need a scientific understanding of their pharmacology, quantifiable effects and potential adverse effects. Illicit drug users select drugs with particular pharmacokinetic parameters and pharmacodynamic properties. Generally, rapid absorption, rapid entry into the central nervous system, high bioavailability, short half-life, small volume of distribution and high free drug clearance are pharmacokinetic characteristics which predict a high potential for harmful use because these factors increase positive reinforcement. Drug users adapt the method and route of drug administration to optimise the delivery of the drug to the brain while attempting to maximise the bioavailability of the drug. Inhalation and smoking are the routes of administration which allow the most rapid delivery of drug to the brain, while intravenous injection maximises the bioavailability of an administered drug. Each route of administration results in attendant complications related to mucosal damage, carcinogenesis and risk of infection. Negative reinforcement or withdrawal is a major drive to recurrent use. Many illicit drugs have pharmacological features that promote dependence, including long half-life, low free drug clearance and sufficient drug exposure to allow development of tolerance. The preventive or reductive pharmacotherapeutics of illicit drug use makes use of several subsets of agents: those which act on the same receptor or system as the illicit drug (such as methadone), those which produce an adverse reaction on consumption of the illicit drug (such as disulfiram) and those which symptomatically attenuate illicit drug withdrawal symptoms (such as clonidine). Many new agents are being trialled as potential preventive or reductive agents. It is important to consider pharmacotherapy as only one potential part of the treatment of illicit drug users. The complications of illicit drug use present many therapeutic challenges. As with all patients consuming multiple drugs, illicit drug users are prone to developing drug interactions. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the additive effects of different drugs on the central nervous system. However, alcohol, cocaine, disulfiram, methadone and tricyclic antidepressants may be involved in important pharmacokinetic interactions. Of these the effect of long term alcohol consumption in increasing the hepatotoxicity of paracetamol and of cytochrome P450 3A microsomal enzyme stimulating drugs in diminishing the efficacy of methadone are the most commonly encountered.

Pharmacokinetics of a series of bis(methanesulphonamido-arylalkyl)amines in the beagle dog

1. The pharmacokinetics of three closely related analogues of dofetilide have been investigated in the beagle dog. These have been compared with those of dofetilide and related to physicochemical properties and structural features of the molecules. 2. Following intravenous administration, the four compounds exhibit elimination half-lives ranging from 4.6 to 19 h. This range is due to changes in both volume of distribution and plasma clearance across the series. 3. In vitro plasma protein shows a relationship to lipophilicity within this series. Protein binding increasing from 54% for dofetilide, the least lipophilic compound (log D7.4 = 0.73) to 92% for the most lipophilic analogue (log D7.4 = 2.07). There is a trend for a decrease in the volume of distribution with increased plasma protein binding. 4. Plasma clearance values range from 2.4 to 10.2 ml/min/kg and are comprised of renal and non-renal components. Renal clearance ranges fro 0.11 to 2.9 ml/min/kg and shows an inverse correlation with and lipophilicity of the compounds. Values for the renal clearance of unbound drug suggest that only the most lipophilic derivative (III), has sufficient membrane affinity to undergo tubular reabsorption. 5. Non-renal clearance of either total or free drug shows no relationship with lipophilicity. Highest values are observed for the two compounds with a methyl substituent on the tertiary amine and lowest values for the two compounds in which the tertiary amine is incorporated into a 7-membered ring. In vitro metabolism in dog liver microsomes also shows increased lability for the two N-methyl compounds. The N-desmethyl metabolite is the major product in both cases.

Research Articles: Pharmacokinetics of Promazine in Patients with Hepatic Cirrhosis-Correlation with a Novel Galactose Single Point Method

We examined promazine pharmacokinetics in nine patients with hepatic cirrhosis and in six healthy subjects. A specific and sensitive HPLC method was used to measure promazine concentrations in plasma, plasma water (free drug), red blood cells, and urine after oral administration of promazine (2 × 50mg tablet). There were highly significant reductions in total plasma clearance (p< 0.01), free drug total plasma clearance (p< 0.01), metabolic clearance (p< 0.01), metabolic clearance of free drug (p < 0.01), and fraction bound (p < 0.01) in the cirrhotic patients. The elimination half‐life and the area under the plasma concentration–time curve were significantly increased (p< 0.001 andp< 0.05, respectively) in the cirrhotic patients. However, the overall excreted promazine in urine, time to the promazine peak concentration, distribution half‐life, renal clearance, apparent volume of distribution, and the promazine concentration ratio between plasma and red blood cells were not different. Thus caution is needed in using promazine for patients with hepatic cirrhosis. A newly developed galactose single point (GSP) method was applied to quantitatively measure the residual liver function in cirrhosis patients and successfully correlated it with promazine elimination half‐life (r = 0.770,p< 0.01), total plasma clearance of free drug (r= 0.899,p< 0.005), metabolic clearance of free drug (r0.902,p< 0.005), and plasma protein binding (r= 0.822,p< 0.005). GSP may be a convenient index for promazine routine dosage adjustment in patients with liver cirrhosis. Further studies are needed for developing GSP in to a routine index for drug dosage adjustment in metabolically impaired patients.

The Pharmacokinetics of Zileuton in Healthy Young and Elderly Volunteers

The effects of age and gender on the single and multiple dose pharmacokinetics of zileuton have been examined in a phase I nonblinded study. A total of 27 healthy volunteers were evaluable, 9 in the young group (age range 20 to 40 years; 5 males and 4 females) and 18 in the elderly group (range 65 to 81 years; 9 males and 9 females). A single oral dose of zileuton 600mg was given to all volunteers on day 1 of the study and at 6-hour intervals from days 3 to 7. Analysis of variance showed slight but significant decreases in the mean apparent clearance of total and free drug in the healthy elderly population after a single zileuton dose, but no significant age-related differences after multiple 6-hourly doses. Similarly, zileuton peak and trough plasma concentrations, and values for half-life, volume of distribution and protein binding were not significantly affected by age after either a single dose or multiple administration. Moreover, gender effects on the pharmacokinetics were also absent after correction for bodyweight differences. From the results of the present study, it is concluded that there is no pharmacokinetic basis for alteration of zileuton dosage schedules in elderly patients.

Effects of Age on the Pharmacokinetics of Piroxicam in Rats

This study examined the effects of age on the pharmacokinetics of piroxicam in rats. Two groups of rats, aged 5 and 24 months, were administered 1mg of piroxicam per kg intravenously, and blood samples were withdrawn for up to 120h. Protein binding studies, with pooled serum from each age group were also performed. Piroxicam concentrations were determined by HPLC analysis, and pharmacokinetic parameters were’ characterized by area-moment analysis. Plasma piroxicam concentrations declined in both age groups in a biexponential fashion, with half-lives of 5.9 ± 0.7h (mean ± SD) in the young rats and 30.6 ± 9.9h in the old rats. Total clearance in the young rats was 0.048 ± 0.012 L/h/kg, whereas that in the old rats was 0.021 ± 0.003 L/h/kg. The steady-state volume of distribution in the young rats was 0.42 ± 0.05 L/kg, and that in the old rats was 0.56 ± 0.10 L/kg. There was a statistically significant difference between these parameters calculated for each age group. Piroxicam is a highly plasma protein-bound drug; the fraction unbound in the young rats was determined to be 0.067 ± 0.022, and that in the old rats was determined to be 0.134 ± 0.065, or twice that in the young rats. Differences in protein binding were due, in part, to a 20% decreased albumin concentration in the old rats; however, there was also a decrease in the number of binding sites and/or the binding affinity with aging. Clearance of free drug in the young rats was 0.73 ± 0.18 L/h/kg, and that in the old rats was 0.15 ± 0.02 L/h/kg; the steady-state volumes of distribution for unbound drug were determined to be 6.27 ± 0.78 L/kg for the young rats and 4.18 ± 0.75 L/kg for the old rats. These differences were significantly different. Thus, piroxicam exhibited an age-related disposition in rats.

EFFECTS OF DIFFERENT HEPATIC PATHOLOGIES ON DISPOSITION OF ALFENTANIL IN ANAESTHETIZED PATIENTS

We have studied the influence of different hepatic pathologies on the disposition of alfentanil in 23 unpremedicated patients (six healthy control subjects, six patients with liver dysfunction of alcoholic aetiology and 11 patients with non-alcohol related liver disease). All patients received a bolus of alfentanil 500 micrograms i.v. as supplement to 67% nitrous oxide and isoflurane in oxygen anaesthesia. Plasma drug concentrations were measured in venous blood samples at intervals up to 24 h by radio-immunoassay and protein binding was determined by equilibrium dialysis. Kinetic estimates were determined using non-compartmental analysis. Patients with non-alcoholic liver disease had lesser plasma clearance (114.8 (range 66.8-213.5) ml min-1) than the alcoholic group (158.8 (100.0-220.7) ml min-1) or controls (187.4 (125.2-269.5) ml min-1). In all three groups, there was considerable intersubject variability, with a bimodal distribution in the non-alcoholic group. This group also had a smaller apparent volume of distribution at steady state. Mean residence time was prolonged in the alcoholic group compared with controls (284.9 (217.8-362.2) min vs 226.8 (201.2-250) min). Protein binding was decreased in the alcoholic group compared with controls (84.9 (SD 4.2)% vs 89.3 (2.1)%); this was attributable to a lesser plasma alpha 1-acid glycoprotein concentration (0.55 (0.18) g litre-1 vs 0.89 (0.21) g litre-1). Free drug clearance was reduced in both liver dysfunction groups compared with controls.

Propranolol Disposition in the Rat: Variation in Hepatic Extraction with Unbound Drug Fraction

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three-to fourfold as albumin and α1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.

Stereoselective pharmacokinetics of disopyramide and interaction with cimetidine.

The pharmacokinetics of each of the enantiomers of disopyramide were examined after i.v. bolus administration of 150 mg racemic drug in a randomized cross-over study before and after the administration of cimetidine 400 mg twice daily orally. Clearance and volume of distribution (Vz) of total drug were significantly (P less than 0.001) higher for the R-(-) enantiomer than the S-(+) enantiomer (7.9 vs 4.6 l h-1 and 89 vs 50 l, respectively), whereas no significant difference in half-life could be demonstrated. The clearance of free drug was significantly (P less than 0.05) higher for the S-(+) enantiomer than that of the R-(-) enantiomer (34.6 +/- 5.4 l h-1 vs 27.2 +/- 5.6 l h-1), whereas no significant enantioselective difference in unbound volumes of distribution (258 +/- 38 l vs 226 +/- 42 l) could be demonstrated. Coadministration of cimetidine did not alter the pharmacokinetics of disopyramide. A significant concentration- or time-related decrease in the renal clearance of each of the enantiomers measured with respect to total drug in serum was observed, whereas renal clearances of the free enantiomers were similar.

Mitomycin C-loaded microcapsules in the treatment of colorectal liver metastases. Pharmacokinetics of regionally administered particulate chemotherapy

Microencapsulated mitomycin C has been used for the treatment of intrahepatic tumors in Japan, but there have been no reports of its use in western countries. In this study, the pharmacokinetic profile of intrahepatic arterial mitomycin C microcapsules is reported. Regional mitomycin C was administered to six patients, both in the microencapsulated form and in solution. The clearance (140 +/- 31 1/hour, mean +/- SD) and half-life of drug in plasma (0.39 +/- 0.03 hours), and volume distribution (246 +/- 23 1) were significantly higher, and peak drug concentrations (80 +/- 75 ng/ml) significantly lower with the microencapsulated preparation than with the free drug (clearance, 46 +/- 8 1/hour; half-life, 0.11 +/- 0.02 hours; volume distribution, 33 +/- 4; peak drug concentration, 812 +/- 423 ng/ml), on Student's t testing (P less than 0.05). The results show that very little systemic exposure is associated with the microencapsulated form of mitomycin C. Dose escalation should be feasible without increasing systemic toxicity.

Pharmacokinetics of promazine: I disposition in patients with acute viral hepatitis B

Concentrations of promazine in plasma, plasma water, red blood cells, and urine were measured after oral administration of the drug to six patients during and after apparent recovery from the acute phase of viral hepatitis B. None of the promazine pharmacokinetic parameters were significantly different during and after the acute phase; these parameters included clearance, free drug clearance, metabolic clearance, volume of distribution, distribution and elimination half-life values, plasma protein binding, and per cent excreted in the urine. During the acute period of the illness, SGOP, SGPT, alkaline phosphatase, and total bilirubin were increased in all patients; they returned to within or near the upper limits or normal after recovery. Despite the unchanged promazine disposition, four out of six patients had more severe promazine side-effects, such as sedation, postural hypotension, and dizziness during the acute phase of the illness. This study suggests that promazine disposition was not significantly altered as a consequence of viral hepatitis. However, the pharmacodynamic effects of promazine were changed significantly. Care must be taken with patients who are taking promazine during the acute phase of viral hepatitis B.

The use of pharmacokinetic models in the development and evaluation of site‐specific drug delivery systems

AbstractThe influence of the pharmacokinetics of drug‐carrier conjugates and free drug and of the pharmacodynamics of therapeutic and toxic responses on the potential for successful targeting is discussed. A simple physiologically based compartmental model is used to explore the potential of drug‐targeted systems versus conventional administration. The major kinetic factors affecting the therapeutic advantage of targeted systems are the blood flow to the target site, the systemic clearance of free drug and the selectivity of release of drug from its carrier. A model independent analysis based on linear systems theory using a recirculating model of drug disposition is also described.

Clinical Pharmacokinetics of Non-Opiate Abused Drugs

The present review discusses the available data on the kinetic properties of non-opiate abused drugs including psychomotor stimulants, hallucinogens and CNS-depressants. Some of the drugs of abuse reviewed here are illicit drugs (e.g. cannabis, cocaine), while others are effective pharmacological agents but have the potential to be abused (e.g. benzodiazepines). Although some of the drugs mentioned in this review have been in use for centuries (e.g. caffeine, nicotine, cocaine, cannabis), knowledge of their kinetics and metabolism is very recent and in some cases still incomplete. This is partially due to the difficulties inherent in studying drugs of abuse in humans, and to the complex metabolism of some of these drugs (e.g. cannabis, caffeine) which has made it difficult to develop sensitive assays to determine biological pathways. Although drugs of abuse may have entirely different intrinsic pharmacological effects, the kinetic properties of such drugs are factors contributing to abuse and dependence. The pharmacokinetic properties that presumably contribute to self-administration and drug abuse include rapid delivery of the drug into the central nervous system and high free drug clearance. Kinetic characteristics also play an important role in the development of physical dependence and on the appearance of a withdrawal syndrome: the longer the half-life, the greater the likelihood of the development of physical dependence; the shorter the half-life, the earlier and more severe the withdrawal. The balance between these 2 factors, which has not yet been carefully studied, will also influence abuse patterns. The clinical significance of kinetic characteristics with respect to abuse is discussed where possible.

Pharmacokinetics of Alfentanil in Chronic Renal Failure

The pharmacokinetics of alfentanil were studied during general anesthesia in nine patients with renal failure and in ten patients with normal renal function. All patients received 0.05 mg/kg alfentanil as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 8 hr, using a specific radioimmunoassay technique. Protein binding was measured by equilibrium dialysis. Elimination half-life and plasma clearance were similar in both groups. The volume of distribution at steady state was greater (P less than 0.02) in patients with renal failure (405 +/- 86 ml/kg) than in patients with normal renal function (281 +/- 97 ml/kg). Patients with renal failure had a higher (P less than 0.01) alfentanil plasma free fraction (0.19 +/- 0.06) than patients with normal renal function (0.11 +/- 0.03). When kinetic parameters were corrected for protein binding, the unbound volume of distribution and the free drug clearance were unchanged in patients with renal failure. These results suggest that the modification of alfentanil free fraction in renal failure does not induce any change in elimination but may influence the distribution of alfentanil.

Pharmacokinetic determinants of drug abuse and dependence. A conceptual perspective.

Drugs that produce physical dependence or have similar pharmacological profiles to highly abused drugs are unlikely to be considered acceptable for marketing. Thus, the prediction of abuse and dependence becomes an important issue in the development of new psychotropic drugs. Both pharmacokinetic and non-pharmacokinetic factors play an important role in predicting dependence and abuse liability of drugs. Evidence for the importance of pharmacological factors includes: the demonstration of drug binding to receptors of abused drugs; tolerance; ability to maintain self-administration; and spontaneous or antagonist precipitated withdrawal. The pharmacokinetic properties that presumably contribute to persistent self-administration and abuse include rapid delivery of drug to the central nervous system (CNS), rapid absorption, low protein binding and high free drug clearance. The pharmacokinetic properties of a drug associated with dependence will include long half-life, low free drug clearance and presence of the drug in the body at high enough concentrations and for sufficient time to permit tolerance to develop. These properties have important clinical implications for treatment and research in the area of abuse and dependence liability of psychoactive drugs.