Prolonged Elimination Research Articles

Pharmacokinetics of Fentanyl in Children With Renal Disease

Two cases of fentanyl anesthesia in children with renal diseases are described. In a case of end stage renal failure, the pharmacokinetic parameters during cardiac surgery were similar to 18 children from the same age group with normal renal function. In a case of Wilm's tumor, there was an unusually prolonged elimination half-life of fentanyl and smaller distribution volume as compared to pediatric parameters during fentanyl anesthesia.

Phenytoin disposition in obesity. Determination of loading dose.

Fourteen obese subjects (mean body weight, 124 kg; percent of ideal body weight [IBW], 178%) and ten control subjects of normal body habitus (mean body weight, 67 kg; 92% IBW) received 300 mg of phenytoin sodium by ten-minute intravenous infusion. Obese subjects compared with controls had prolonged phenytoin elimination half-life (19.9 v 12.0 hours). Total metabolic clearance of phenytoin was greater in obese than in control groups, although the difference was not significant (59 v 39 mL/min). Phenytoin half-life, inversely proportional to clearance and directly proportional to volume of distribution (Vd), was prolonged in obesity mainly as a result of the increase in Vd in obese subjects (84 v 40 L). Phenytoin loading dose should be calculated on the basis of IBW plus the product of 1.33 times the excess weight over IBW. Very obese individuals will require large absolute loading doses of phenytoin to rapidly achieve therapeutic drug concentrations.

Interpretation of excessive serum concentrations of digoxin in children

Between January 1981 and April 1984, excessive serum concentrations of digoxin (5 ng/ml or higher) were recorded in 47 children, aged 2 days to 16 years. In 10 patients, the high concentrations were measured 9.25 to 48 hours after death and were significantly higher than antemortem levels in all cases (8.3 ± 2.4 (± standard deviation) postmortem vs 3.3 ±1.5 antemortem, <0.0001). In 15 patients (40.5% of the living patients) serum concentrations of 5 ng/ml or higher reflected sampling errors; drug levels were monitored too closely to the administration of a dose. None of these children had toxic manifestations of digoxin. In 10 patients, the excessive concentrations were associated with renal failure and a prolonged elimination half-life ( T 1 2 ) of digoxin; in 3 of these patients, there were signs of digoxin toxicity. Six cases were caused by digoxin overdose (accidental ingestions, pharmacy error and a suicide attempt). In 6 additional cases, the existence of an endogenous digoxin-like substance (EDLS) was shown to contribute to the excessive levels of the drug. One case could be attributed to digoxin-amiodarohe interaction. In 10 of 37 living patients, digoxin toxicity was diagnosed. After excluding the 15 sampling errors and 6 cases with EDLS, this represents 63% of the cases. There was a good correlation between digoxin elimination T 1 2 and serum creatinine concentrations (r = 0.71, p <0.01). The above observations suggest that excessive serum concentrations of digoxin may not necessarily reflect potentially toxic levels. Sampling errors, postmortem determinations and circulating EDLS should be considered as explanations when toxic levels of digoxin are found.

Clinical pharmacokinetics of the angiotensin converting enzyme inhibitors. A review.

The angiotensin converting enzyme inhibitors are an important therapeutic advance in the treatment of patients with hypertension and congestive heart failure. In addition, they are useful pharmacological probes to assess the contribution of the renin-angiotensin system to circulatory homeostasis. Captopril was the first angiotensin converting enzyme inhibitor approved for use in patients with hypertension and congestive heart failure. It is rapidly absorbed from the gastrointestinal tract, with detectable plasma concentrations apparent as early as 15 minutes. The extent of absorption is between 60 and 75% of an oral dose and peak plasma concentrations occur after approximately one hour. Captopril is primarily excreted by the kidneys via renal tubular secretion. Renal excretion is rapid, with 90% completed in the first 4 hours. The elimination half-life for unchanged captopril is about 1.7 hours and is markedly increased in the presence of renal insufficiency. Once absorbed, captopril is extensively metabolised to several forms, including a disulphide dimer of captopril, a captopril-cysteine disulphide, and other mixed disulphides with endogenous thiol compounds. It is probable that captopril and its pool of metabolites undergo reversible interconversions. Pharmacokinetic properties of captopril in patients with uncomplicated hypertension appear to be the same as in healthy subjects. However, long term administration of captopril leads to increased concentrations of total captopril, probably from the accumulation of captopril metabolites. Despite the number of potential influences on pharmacokinetic properties in patients with congestive heart failure, due to the many abnormalities in gastrointestinal tract oedema and reductions in splanchnic and renal blood flow, the available data suggest that its pharmacokinetic properties in patients with congestive heart failure resemble those in healthy subjects. However, additional data are necessary to confirm this. Enalapril is the second angiotensin converting enzyme inhibitor to become available. Enalapril is a prodrug that is well absorbed from the gastrointestinal tract, with 60 to 70% of an oral dose being absorbed. However, enalapril must be converted by hepatic esterases to the active form, enalaprilat. After the oral administration of enalapril, the tmax for enalapril is one hour, but for enalaprilat it is 4 hours. There is a prolonged terminal elimination phase with enalaprilat being detectable as late as 96 hours after dosing. Thus, enalapril has a much longer duration of action than captopril. Like captopril, enalapril is primarily excreted by the kidneys.(ABSTRACT TRUNCATED AT 400 WORDS)

Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives.

The effect of chronic (greater than 3 months) administration of low-dose oestrogen-containing (less than 50 micrograms oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.7501/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 micrograms/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.

Pharmacokinetic properties and bioavailability of methimazole.

The pharmacokinetics of methimazole following therapeutic doses were studied in healthy subjects, in thyrotoxic and hypothyroid patients before and after treatment to euthyroidism, and in patients with renal or hepatic insufficiency, using a highly sensitive gas chromatographic-mass spectrometric assay. Following intravenous administration of 10mg to healthy subjects, methimazole had an initial distribution half-life (t1/2 alpha) of 0.10 to 0.23 hours and an elimination half-life (t1/2 beta) of 4.9 to 5.7 hours. The absolute bioavailability after oral administration of 10mg methimazole in the fasting state was high, with a mean of 93%. The pharmacokinetic profiles showed small interindividual variations, although one of the hypothyroid patients had a rapid elimination half-life, in both the hypothyroid and euthyroid state (2.6 and 2.4 hours, respectively). The elimination rate was not enhanced in the thyrotoxic patients but was slightly prolonged in the hypothyroid patients. There was no influence of renal insufficiency, but a prolonged elimination half-life was observed in patients with hepatic failure, the prolongation being proportional to the degree of impairment. Thus, the pharmacokinetics of methimazole are relatively simple with small interindividual variations. In general, there are no pharmacokinetic reasons to adjust dosage in the treatment of thyrotoxicosis, except in the rare case of concomitant advanced hepatic insufficiency.

Penetration and clearance of cefoperazone and moxalactam in pleural fluid.

The penetration of cefoperazone and moxalactam into pleural fluid was studied in 11 patients after intravenous infusion of 2-g doses of these agents. Clearance of these agents from pleural fluid was studied in seven patients after instillation of 1-g doses into the pleural space. The concentrations in pleural fluid after intravenous infusion of 2-g doses reached a peak of 7 to 25 micrograms/ml for cefoperazone and 9 to 35 micrograms/ml for moxalactam at 4 to 6 h after administration. These levels exceeded reported MICs for most susceptible organisms. The elimination half-life of both agents was about two to five times longer in pleural fluid than in serum. These prolonged elimination rates of both agents might be of great advantage for killing bacteria in the pleural space.

Pharmacokinetics and Pharmacodynamics of d-Tubocurarine and Metocurine in the Elderly

The effects of age (older than 70 yr) on the pharmacokinetics and pharmacodynamics of d-tubocurarine (dTc) and metocurine (MTc) were evaluated in studies of 21 patients aged 70-87 and 21 patients aged 29-59. There was a significant difference in the pharmacokinetic parameters of all elderly patients compared with younger controls. With both dTc and MTc, the elderly exhibited a decreased plasma clearance, decreased initial volume of distribution, decreased volume of distribution, and a prolonged elimination half-life. After 0.3 mg/kg of dTc, the times for 50% return of twitch and recovery index (25-75% return of twitch response) in the elderly were significantly longer than in the young (P less than 0.02). A similar observation was made for the elderly patients receiving 0.15 mg/kg of MTc. No significant difference was seen in the log plasma concentration-twitch response relationship between 20-80% paralysis in young and in elderly patients receiving dTc. There was a similar lack of significant difference between the log plasma concentration-twitch response lines for elderly and young patients receiving MTc. Because there was no difference between the plasma concentration-response relationships in the elderly and young, altered sensitivity to dTc or MTc cannot explain the longer duration of action seen in the elderly. The most likely explanation for this difference is the altered pharmacokinetics of these two drugs in the elderly.

Cefonicid: a long-acting, second-generation cephalosporin. Antimicrobial activity, pharmacokinetics, clinical efficacy and adverse effects.

Cefonicid is a new second-generation cephalosporin with a broad antimicrobial spectrum of activity and a prolonged serum elimination half-life. It has good in vitro activity against methicillin-sensitive Staphylococcus aureus, nonenterococcal streptococci, Hemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis and many of the commonly isolated Enterobacteriaceae. Organisms usually resistant to cefonicid include species of Pseudomonas, Serratia, Acinetobacter and Providencia, and Bacteroides fragilis. The drug is 98% protein bound in human serum, which probably contributes to its significant reduction of antimicrobial activity measured in serum. Limited clinical trials have demonstrated it to be effective for surgical prophylaxis and for treating infections of the urinary tract, lower respiratory tract and bone. Failures have been reported in treatment of soft tissue infections and endocarditis caused by S. aureus. A potential cost reduction may be achieved by administering a single daily dose of cefonicid for established infections or a single preoperative dose for effective surgical prophylaxis instead of multiple-dose regimens of other, similar agents.

Propranolol interactions with diazepam, lorazepam, and alprazolam.

Healthy subjects received single doses of diazepam (5 to 10 mg iv), lorazepam (2 mg iv), or alprazolam (1 mg orally) on two occasions, once in the control state and once with propranolol, 80 mg three times a day. Compliance with the propranolol regimen was verified by measurement of serum propranolol levels (overall means: 100 ng/ml) and by reduction in sensitivity to intravenous metaproterenol to one-thirtieth that of the control value. Propranolol prolonged diazepam elimination t1/2 (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168-hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 micrograms/ml . hr). Propranolol had no significant effect on lorazepam t1/2 (13.2 and 12.7 hr) or clearance (1.33 and 1.36 ml/min/kg), nor on alprazolam t1/2 (15.9 and 18.5 hr) or clearance (1.1 and 0.8 ml/min/kg). Thus propranolol induces a small but significant reduction in clearance of diazepam, biotransformed mainly by the oxidative reaction of N-demethylation. Propranolol does not impair lorazepam clearance by glucuronide conjugation nor that of alprazolam by aliphatic hydroxylation.

Pharmacokinetics of Pentobarbital, Quinidine, Lidocaine, and Theophylline in the Thermally Injured Rat

Previous studies have shown that rats with 15% third-degree burns show a severe depression in various in vitro hepatic drug-metabolizing enzymes. This effect was assessed in vivo by measuring the disposition of four liver-metabolized drugs in 16% third-degree burned rats at 7 d postburn. Compared with pair-fed control rats, pentobarbital demonstrated a significantly prolonged clearance and elimination half-life without a change in volume of distribution. Quinidine demonstrated a significantly increased volume of distribution and a significantly decreased clearance without a change in elimination half-life. Lidocaine showed a significantly increased volume of distribution. Theophylline, which is only 50% metabolized in the rat, showed no changes in any pharmacokinetic parameters. The free drug fractions of quinidine and lidocaine were found to be significantly decreased at 1 d postburn and normal at 7 d postburn. These results warrant pharmacokinetic studies in human burn patients.

Altered d-tubocurarine disposition during cardiopulmonary bypass surgery.

Kinetics of the neuromuscular blocker d-tubocurarine (dTc) were investigated in 13 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 1 hr before CPB surgery, each received dTc as an intravenous bolus of 0.6 mg/kg and a maintenance infusion of 3 micrograms/kg/min. dTc plasma concentration-time data before CPB did not differ from those reported in normal surgical patients. There was an abrupt discontinuity in the plasma concentration-time profile with the onset of CPB, and both total and free plasma concentrations increased 400% during the period of CPB. Although computer simulations suggest that these rises in dTc plasma concentrations can be attributed to contraction in central compartment volume, there also was decreased renal and total plasma clearance of dTc together with a prolonged elimination 1 1/2, which suggests that clearance processes of dTc are also altered as a result of CPB. A 27% rise in dTc free fraction in plasma during CPB could be attributed to hemodilution associated with the CPB procedure itself. Lower doses of dTc will need to be used in patients undergoing surgery that involves CPB unless the concentration-effect relationship for dTc is so altered that higher concentrations are needed to elicit the same response as in normal patients.

PHARMACOKINETICS OF ALCURONIUM IN ELDERLY PATIENTS UNDERGOING TOTAL HIP REPLACEMENT OR AORTIC RECONSTRUCTIVE SURGERY

The pharmacokinetic behaviour of alcuronium was studied in three patients undergoing resection of an aortic aneurysm, and in another two patients undergoing total hip replacement (group I). A control group of five elderly patients undergoing relatively minor surgery was included (group II). In group I patients, the values of the pharmacokinetic parameters such as plasma clearance, elimination half-life and the apparent volume of distribution of the drug were found to be comparable to those obtained in normal young patients in previous studies. The group II patients, however, were found to have a prolonged elimination half-life as a result of reduced plasma clearance, possibly an age-related effect. The differences between these two groups of patients may be explained by the differences in the extent of haemorrhage and fluid replacement or changes in blood circulation, or both. However, alcuronium must still be used cautiously in both groups of patients, especially in the light of a recent finding that patients undergoing aortic reconstructive surgery have a high frequency of functional renal failure after operation.

Amiodarone: Prolonged elimination following cessation of chronic therapy

Amiodarone: Prolonged elimination following cessation of chronic therapy

Interaction of cimetidine with oxazepam, lorazepam, and flurazepam.

The influence of cimetidine coadministration, 300 mg every 6 hours, on the kinetics of single oral doses of oxazepam (30 mg), lorazepam (2 mg), and flurazepam (30 mg) was evaluated in healthy volunteers. Cimetidine had no significant effect on the peak plasma concentration or the time of peak concentration for either oxazepam, lorazepam, or desalkylflurazepam (formed from flurazepam). Cimetidine likewise did not alter the elimination half-life of oxazepam (9.4 hours) or lorazepam (11.6 hours), and did not change total AUC for lorazepam. Oxazepam AUC was increased an average of 10 per cent by cimetidine (P less than 0.02). In contrast, cimetidine prolonged desalkylflurazepam elimination half-life (141 vs. 94 hours, P less than 0.1) and increased AUC an average of 65 per cent (P less than 0.05). Thus, cimetidine has little or no influence on the absorption or disposition of oxazepam and lorazepam, two benzodiazepines biotransformed by glucuronide conjugation. However, cimetidine slows the elimination of flurazepam's metabolite, desalkylflurazepam, which is biotransformed by oxidation.

ACCUMULATION OF FUROSEMIDE FOLLOWING FREQUENT REPEATED DOSES IN NEWBORN INFANTS

Furosemide (F) may have a reduced volume of distribution and prolonged plasma clearance following frequent repeated doses of F in newborn infants. To test whether repeated doses result in plasma accumulation of the drug, four neonates (x̄ bt wgt 1140 g, range: 810-1645), (x̄ gestational age 27 5/7 wks, range: 26-30 wks) with normal renal function were given F, 1 mg/kg/dose IV bolus every 12 hours for 4 doses and maintained normally hydrated during the study period. Serum F levels in mg/l (see table) were measured by HPIC 1 hr after each bolus. Serum F concentration increased with repeated doses beyond that expected for the reported plasma t½ of 7-19 hrs. Serum F concentration after the second dose was significantly higher than F level after the initial dose (p<0.01). This accumulation of F in the serum of the neonate with repeated doses may reflect delayed plasma clearance and contraction of the volume of distribution superimposed on a prolonged elimination rate. Caution should be observed when given frequent repeated doses of F to newborn infants.

Papaverine disposition in cardiac surgery patients and the effect of cardiopulmonary bypass.

Cardiac surgery involving cardiopulmonary bypass (CPB) causes substantial physiologic changes which may potentially alter the pharmacokinetic properties of drugs used during and after the procedure. Studies with fentanyl have implied a relationship between prolonged elimination half-lives following CPB and decreased liver perfusion during and after the procedure. To further test this hypothesis, the effects of CPB on the pharmacokinetics of papaverine, a coronary vasodilator currently being added to the cardioplegic solution to prevent vasospasm, were studied. The drug was given to two groups of patients, one (n = 6) undergoing surgery with and one (n = 5) without CPB, the latter serving as controls. Plasma papaverine concentrations declined biexponentially in the control patients with a mean elimination half-life of 1.30 +/- 0.25 h, total plasma clearance of 13.8 +/- 3.75 ml/min/kg, volume of distribution of 1.52 +/- 0.45 l/kg and volume of distribution, steady-state, of 0.992 +/- 0.530 l/kg. For the CPB group, only half-life was estimated, and averaged 2.77 +/- 0.28 h, significantly greater (p less than 0.01) than that in the controls. These results further confirm the increased half-lives seen with other hepatically cleared drugs following CPB and have implications in the clinical management of patients given drugs eliminated in this manner.

Clinical pharmacokinetics of the antituberculosis drugs.

The quantitative aspects of the disposition in man of 12 antituberculosis drugs [isoniazid, rifampicin, (rifampin), ethambutol, para-aminosalicylic acid, pyrazinamide, streptomycin, kanamycin, ethionamide, cycloserine, capreomycin, viomycin and thiacetazone] are reviewed. Isoniazid appears to be the only agent for which plasma concentrations and clearance are related to hereditary differences in acetylator status and for which there is an appreciable 'first-pass' effect. Recent data cast doubt on the suggestion that isoniazid may be more hepatotoxic for rapid as opposed to slow acetylators. Continuous administration of rifampicin leads to induction of enzymes in the liver with a concomitant decrease in maximum plasma concentrations, the time required to achieve this level, elimination half-life, and area under the plasma concentration-time curve (AUC). Coadministration of para-aminosalicylic acid leads to increases in the serum concentrations and elimination half-life of isoniazid. With a few exceptions, the metabolites of the antituberculosis drugs are devoid of antimicrobial activity; the exceptions are 25-desacetylrifampicin which accounts for approximately 80% of the drug's antimicrobial activity in human bile, the acetylated and glycylated metabolites of para-aminosalicylic acid, and the sulphoxide metabolites of ethionamide. The effect of renal impairment is relatively unimportant for the excretion of isoniazid, rifampicin and para-aminosalicylic acid, but the elimination half-life of streptomycin increases to 100 hours when the blood urea nitrogen level is greater than 100mg/100ml, and ototoxicity is strikingly more frequent. In states of malnutrition, such as kwashiorkor, the protein binding of para-aminosalicylic acid decreases from 15% to essentially zero and in the case of ethionamide and streptomycin binding decreases by 6% and 16% respectively. Of the data concerning age-related effects, most notable are the prolonged elimination half-life of isoniazid in neonates (up to 19.8 hours), and the lower peak serum concentrations of rifampicin in children of one-third to one-tenth those of adults following a similar dose on a weight basis. For kanamycin, the maximum plasma concentration varies inversely with age but is not influenced by birthweight; however, the clearance is directly dependent upon birthweight and postnatal age. For the elderly, age is an insignificant factor for the elimination of isoniazid when compared with young adults of similar acetylator status, and the metabolism of rifampicin may be considered globally unaltered in this age group.(ABSTRACT TRUNCATED AT 400 WORDS)

Atenolol elimination in the neonate.

The elimination of the cardioselective beta-adrenoceptor antagonist atenolol has been studied in 35 neonates by measuring drug concentration in cord blood and in blood obtained at 24 h by heel stab. Elimination rate was assessed by calculating the slopes of lines joining these two concentration points. The slopes had a mean of 0.043 h-1 (equivalent to a half-life of 16 h) and were normally distributed with 95% of values being in the range 0.02-0.066. There was no relationship between slope and neonatal weight or skinfold thickness, but most babies were at term and the range of these indices was narrow. Babies who developed a bradycardia had cord atenolol concentrations and slopes which did not differ significantly from those in babies without bradycardia. We conclude that atenolol elimination in the neonate is reduced when compared to adults. This prolonged elimination is consistent with the physiological characteristics of this age group and with previous observations on drugs eliminated by renal excretion.

Pharmacokinetic Studies on Atropine with Special Reference to Age

VIRTANEN, R.; KANTO, J.; IISALO, E.; IISALO, E. U. M.; SALO, M.; SJOVALL, S. Author Information