Donald Perrier

Thiopental disposition in lean and obese patients undergoing surgery.

The effect of obesity on the disposition kinetics of thiopental was studied in seven morbidly obese (age 25 to 46 years) and eight age-matched lean patients (age 25 to 43 years), undergoing primarily abdominal surgery. Based upon total (bound + free) thiopental concentrations, the average (±SD) volumes of distribution in the terminal disposition phase and at steady-state (Vβ and Vss) were significantly larger in the obese (7.94 ± 4.55 1/kg and 4.72 ± 2.73 1/kg, respectively) than in the age-matched lean patients (1.95 ± 0.63 1/kg and 1.40 ± 0.46 1/kg, respectively). Clearance of total thiopental, normalized for total body weight was not significantly different between the obese (0.18 ± 0.081 · h−1 · kg−1) and lean patients (0.2 ± 0.06 1 · h−1 · kg−1). However, total body clearance not normalized for total body weight was significantly larger in the obese (24.98 ± 14.87 1/h) than in the lean patients (11.86 ± 3.66 1/h). The elimination half-life of thiopental was significantly longer in the obese (27.85 h) than in the lean patients (6.33 h) and (his difference was primarily a function of the larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8 per cent to 27.6 per cent) was not correlated with the degree of obesity. The most appropriate means of comparing intrinsic metabolizing capacity (i.e., normalized vs. non-normalized for weight) between lean and obese subjects remains unresolved.

Bleomycin pharmacokinetics in man: II. Intracavitary administration

Disposition of bleomycin was studied in plasma and urine (14 patients) and ascites fluid (2 patients) after intraperitoneal (IP) and intrapleural (IPl) administration, by radioimmunoassay. Peak plasma bleomycin concentrations after 60 U/m2 in 12 patients ranged between 0.4 and 5.0 mU/ml. For those patients with creatinine clearances greater than 50 ml/min the composite terminal phase bleomycin plasma half-lives (±SD) for three ‘IPl’ and six ‘IP’ patients were 3.4±0.3 and 5.3±0.4 h, respectively. The composite IP plasma half-life was significantly longer than the IPl hal-life (P<0.001) and previously reported IV half-life (t1/2=4.0 ±0.6 h) (P<0.01). In patients with normal renal function, bleomycin excretion during the first 24 h was in most cases lower following intracavitary (IC) than following IV administration (21.7%±8.6% vs. 44.8%±12.6%, respectively) (P<0.005). Comparison of bleomycin plasma concentration time products normalized for dose and half-life for IV and IC administration allowed an estimate that about 45% of the IC bleomycin dosage is absorbed into the systemic circulation. When calculating the total systemic exposure to bleomycin for a patient we suggest using the sum of the IV dose and one-half of the IC dose.

Plasma protein binding and distribution characteristics of drugs as indices of their hemodialyzability

The dialysis clearance, plasma protein binding, and distribution (expressed as volume of distribution) characteristics of a drug were evaluated as predictive indices of the efficiency of hemodialysis in removing drug from the body. Dialysis clearance correlated poorly with the fraction of drug in the body removed by hemodialysis. The best predictive measure of hemodialysis efficiency was obtained by a nonlinear model relating the ratio of the percent of free drug in the plasma and the volume of distribution of the drug to the fraction removed. Knowledge of the binding and distribution characteristics of a drug provides insight into the diatyzability of a drug which in turn may assist in coming to decisions on the necessity of dose adjustments for patients on chronic hemodialysis and the rational use of hemodialysis in the treatment of drug intoxication.

Bleomycin pharmacokinetics in man. I. Intravenous administration.

SummaryDisposition of bleomycin was studied in plasma and urine (14 patients) and ascites fluid (2 patients) after intraperitoneal (IP) and intrapleural (IPl) administration, by radioimmunoassay. Peak plasma bleomycin concentrations after 60 U/m2 in 12 patients ranged between 0.4 and 5.0 mU/ml. For those patients with creatinine clearances greater than 50 ml/min the composite terminal phase bleomycin plasma half-lives (±SD) for three ‘IPl’ and six ‘IP’ patients were 3.4±0.3 and 5.3±0.4 h, respectively. The composite IP plasma half-life was significantly longer than the IPl hal-life (P<0.001) and previously reported IV half-life (t1/2=4.0 ±0.6 h) (P<0.01). In patients with normal renal function, bleomycin excretion during the first 24 h was in most cases lower following intracavitary (IC) than following IV administration (21.7%±8.6% vs. 44.8%±12.6%, respectively) (P<0.005). Comparison of bleomycin plasma concentration time products normalized for dose and half-life for IV and IC administration allowed an estimate that about 45% of the IC bleomycin dosage is absorbed into the systemic circulation. When calculating the total systemic exposure to bleomycin for a patient we suggest using the sum of the IV dose and one-half of the IC dose.SummaryBleomycin plasma decay kinetics and urinary excretion were studied in nine patients after IV bolus injections of 13.7 to 19.9 U/M2. Radio-immunoassay was used to measure bleomycin in plasma and urine samples. The resulting plasma concentration versus time data for each patient and the combined data obtained from all patients were fitted to a multiexponential equation using a nonlinear regression computer program. Pharmacokinetic parameters derived from the mean of all individual patient parameters and the composite of all plasma decay data were similar. Bleomycin initial and terminal plasma half-lives and volume of distribution for all plasma decay data from eight patients with normal serum creatinies were 24.4±4.0 min, 237.5±8.5 min, and 17.3±1.5 L/M2, respectively. Mean 24-h urinary excretion accounted for 44.8±12.6% of the dose in seven patients who had normal serum creatinine values and complete urine collections. The total body clearance and renal clearance in these seven patients averaged 50.5±4.1 ml/min/M2 and 23.0±1.9 ml/min/M2, respectively. One patient with a serum creatinine of 1.5 mg% (normal 0.7 to 1.3 mg%) who was given 15.6 U/M2 had a terminal plasma halflife of 624 min, a volume of distribution of 36.3 L/M2, and 24-h urinary excretion of 11.6% of the dose. We conclude that bleomycin after intravenous bolus injection has a relatively short terminal phase plasma halflife and relatively large urinary elimination.

Effect of dose on phenytoin absorption

To determine the effect of dose on phenytoin bioavailability, a single intravenous 15‐mg/kg dose, single oral doses of 400, 800, and 1,600 mg, and 1,600 mg in divided doses (400 mg every 3 hr) were given to six healthy male subjects. Values of Vmax (maximum elimination rate) and Km (serum concentration at which rate of elimination is one half the maximum rate) from the intravenous dose were used to determine the extent of absorption. Although no statistically significant difference in extent of phenytoin absorption was detected, the time to reach maximum phenytoin serum concentrations increased from 8.4 hr for the 400‐mg dose and 13.2 hr for the 800‐mg dose to 31.5 hr for the 1,600‐mg dose. After the 400, 800, and 1,600‐mg doses and 1,600‐mg divided doses, the serum concentration peaks were 3.9, 5.7, 10.7, and 15.3 mg/l. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to slow dissolution and continued absorption from the colon. Due to prolonged absorption of phenytoin, it may be necessary to use larger oral than intravenous loading doses to achieve the same maximum phenytoin serum concentrations.

Evaluation of a charcoal-sorbitol mixture as an antidote for oral aspirin overdose.

The preparation of charcoal in a 70% sorbitol solution results in a suspension that is more palatable and less gritty than an aqueous slurry of charcoal. Although the charcoal-sorbitol mixture may be slightly less effective in reducing the extent of aspirin absorption compared with a charcoal slurry, it may prove to be of particular value in those cases where acceptance of a charcoal slurry presents a problem.

Phenobarbital Pharmacokinetics and Bioavailability in Adults

Abstract: The pharmacokinetics and bioavailability of phenobarbital were examined in six healthy adult subjects after a 2.6 mg/kg intravenous and a 2.9 mg/kg oral dose. Serum concentrations of phenobarbital were followed by means of a high pressure liquid chromatographic assay for 21 days after drug administration. After the intravenous dose, the mean distribution half‐life was 0.18 hour and the mean elimination half‐life was 5.8 days. Mean total body clearance and mean renal clearance were 3.0 ml/hr/kg and 0.8 ml/hr/kg, respectively. The apparent volume of distribution was 0.60 liter/kg. After administration of phenobarbital tablets, the maximum phenobarbital serum concentration was 5.5 mg/liter at 2.3 hours after the dose. Adjusted absolute availability of phenobarbital from the tablets studied was 94.9 per cent (range 81–111.9 per cent). The elimination half‐life averaged 5.1 days for the oral dose. There was no evidence of autoinduction of phenobarbital elimination over the study period.

Clinical Pharmacokinetics of Digitoxin

SummaryThe disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailabilily. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption.The digitoxin plasma concentration-lime curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analysed. Distribution is complete within 4 to 6 hours and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (>90%) to plasma protein (albumin) with an association constant of 9.62 × 104 litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin.As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and faeces. Metabolism is considered to be the major route of elimination, accounting for about 70% of a dose. While most reports indicate that only 30% of a digitoxin dose is eliminated intact (in urine and faeces) this value may be as high as 48%. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variant in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method.Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing haemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation.Cholestyramine has been shown to reduce digiloxin half-life by interfering with the en-terohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbulazone, phenobarbitone, and phenytoin decrease digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digiloxin half-life.Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25ng/ml are considered to be within the therapeutic range. As with digoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.

Efficacy, Plasma Concentrations and Adverse Effects of A New Sustained Release Procainamide Preparation

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

Allopurinol kinetics and bioavailability - Intravenous, oral and rectal administration

SummarySix normal, healthy adult males received a single dose of allopurinol intravenously, orally in the form of a commercial tablet, and rectally in the form of an extemperaneously prepared suppository (either in a cocoa butter or in polyethylene glycol base). Plasma allopurinol and oxipurinol concentrations were measured over a period of at least 60 h. The following mean (±SD) values were obtained from the intravenous allopurinol experiment: clearance, 9.62±3.49 ml · kg-1 · min-1; Vd, 1.61±0.74 l/kg; t1/2, 1.62 h. Oxipurinol had a mean t1/2 of 16.90 h. The absolute systemic bioavailability of the oral tablet was 67%±23%, while the allopurinol rectal suppositories produced no measurable plasma concentrations of allopurinol or oxipurinol in any of the subjects. Current use of rectal dosage forms as an adjunct in cancer chemotherapy should therefore be re-examined.