Elimination Half-time Research Articles

Tissue distribution of 125I-labelled bovine superoxide dismutase (SOD) in the rat.

Bovine copper/zinc superoxide dismutase (SOD) was labelled with 125I using the chloramine-T method. The tissue distribution of 125I-SOD (dose of SOD 5 mg/kg) was studied with whole-body and microautoradiography at various times after an intravenous injection. The distribution of 125I-SOD showed a remarkable organ specificity in that the localization of the enzyme to the kidneys and the urinary tract completely dominated the autoradiograms. The time pattern of localization of 125I-SOD also gives a clear picture of the renal handling of the enzyme in that, as a consequence of the renal elimination, the enzyme rapidly disappears from the circulation with an elimination half time of about 6 min. Up to 20 min. after the injection, there were high concentrations of 125I-SOD in the renal pelvis, ureter and urinary bladder showing that in addition to renal uptake there was an initial substantial urinary excretion of the enzyme. From the microautoradiography it is clear that the grains were exclusively localized over proximal tubular cells and tended to be concentrated at the luminal rather than the peritubular side of tubule. This would be compatible with renal uptake secondary to glomerular filtration of 125I-SOD, which is what one would expect from the renal handling of a protein with a molecular weight around 31,000 and an isoelectric point around pH 5.4. Pretreatment with a large dose of SOD (88 mg/kg) tended to competitively decrease the renal uptake of labelled SOD after 5 min. and apparently further increase its renal excretion. However, a noticeable renal uptake of 125I-SOD was still apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Elimination of [14C]heptachlor from body stores of lactating ewes treated with ovine growth hormone.

Elimination of [14C]heptachlor from body burdens of sheep was measured using mature ewes nursing single offspring, and the influence of exogenous ovine growth hormone (oGH) on elimination was studied. Six ewes (62 +/- 2.5 kg BW) were dosed (i.p.) once with [14C]heptachlor (2.04 mg/kg Bw; .88 microCi/mg heptachlor) and three were treated additionally with oGH (oGH; 5 mg/d) for 21 d. Three additional ewes served as controls. Excreta were collected each day for 21 d. Milk and blood were collected every 3rd d until ewes were euthanized at d 21. 14C activity was measured in excreta, milk, blood and tissues. Total cumulative activity of [14C]heptachlor and(or) metabolites in excreta (21 d) did not differ (P greater than .20) in ewes given oGH (25 +/- 2%) vs none (23 +/- 2%). Milk yield and protein content were unaffected (P greater than .10) by oGH. Ewes given oGH eliminated 2.2 +/- 2% of total 14C dosage into milk during 21 d, whereas ewes untreated with oGH eliminated 1.3 +/- .2% (P less than .10); total 14C activity eliminated into milk plus excreta was similar for ewes given oGH or none (P greater than .10). For all six ewes, half-times (T1/2) for distribution and elimination of 14C activity (heptachlor and metabolites) were 1.5 d and 11.7 d, respectively. Blood concentrations of 14C activity during 21 d yielded elimination half-time as 23 d. Unlike bovines, which eliminate heptachlor slowly (T1/2 approximately 70 to 80 d) and mainly into milk fat, lactating ovines eliminated heptachlor and(or) metabolites mainly into excreta and about sixfold faster than bovines.

Pharmacokinetics of propylthiouracil in children and adolescents with Graves' disease in the hyperthyroid and euthyroid states.

The pharmacokinetics of propylthiouracil (PTU) was studied in 7 patients having Graves' disease when they were hyperthyroid and then again when they were euthyroid. Two additional euthyroid patients were also studied. The t1/2, Ke, Ka, apparent Vd, AUC and clearance were calculated. Serum T3 and T4 were also measured. PTU had an immediate effect in reducing T3 levels. Although there were intraindividual variations, the mean PTU elimination half-time did not change from the hyperthyroid state (1.47 h) to the euthyroid state (1.53 h). The mean Ka when hyperthyroid (2.12 h-1) was significantly increased (p less than 0.005) compared to when euthyroid (1.00 h-1). The calculated kinetic information indicates that the disposition of PTU in children is similar to that reported in adults.

Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism.

1. The elimination half-time of 25-hydroxyvitamin D in plasma was estimated after intravenous injection of the radioactively labelled metabolite in seven patients with primary hyperparathyroidism before and after excision of a parathyroid adenoma. 2. The elimination half-time of 25-hydroxyvitamin D was significantly shortened in primary hyperparathyroidism and reverted towards normal after parathyroidectomy. 3. The increased metabolic clearance of 25-hydroxyvitamin D in primary hyperparathyroidism was accounted for by an increased excretion of vitamin D-derived inactivation products in the faeces. 4. Enhanced hepatic inactivation of 25-hydroxyvitamin D may be important in the development of vitamin D deficiency in primary hyperparathyroidism.

Systemic availability of o,p’-ddd in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism

The systemic availability of o,p'-DDD was studied in 12 normal dogs and seven dogs with pituitary-dependent hyperadrenocorticism (PDH). The drug was given by mouth at 50 mg kg-1 and plasma o,p'-DDD concentrations were determined by gas-liquid chromatography. First, six normal dogs were given the drug three times at intervals of one week in a Latin square pattern. Systemic drug availability was found to be very poor from intact tablets in fasted dogs, better with pure drug dissolved in maize oil given by stomach tube, and best with ground tablets mixed in oil poured on dog food. Then six normal dogs and five with PDH were given one dose of o,p'-DDD as intact tablets in dog food. Systemic drug availability was good in the normal animals and, for unknown reasons, better in dogs with PDH. The half-time of elimination was shorter in dogs with PDH than in normal ones. There was evidence of a gradual rise in plasma o,p'-DDD concentrations in seven dogs with PDH treated with 25 mg kg-1 every 12 hours for 14 or 20 days. The interaction between food and o,p'-DDD probably contributes to the variation in clinical response of dogs treated with the drug. The efficiency of therapy with o,p'-DDD should be improved considerably by administering the drug with food.

Prognostic importance of systemic clearance of methotrexate in childhood acute lymphoblastic leukemia.

Pharmacokinetic studies of methotrexate have been carried out in 21 children with acute lymphoblastic leukemia diagnosed in 1981. Children were treated with intermediate dose (500 mg/m2) methotrexate in keeping with the 1981 ALL treatment Protocol of the Hungarian Childhood Leukemia Working Group. Of the 21 children, 8 relapsed, and 13 are in continuous complete remission. In the relapsed patients significantly increased systemic clearance of methotrexate was observed at the time of the second methotrexate treatment cycle compared with the calculated value after the first administration of the drug. No such change in the clearance was found in patients who are still in remission. There was no difference between children who relapsed or who are in remission in the elimination half-time of the drug. Age, sex, WBC at diagnosis, and systemic clearance of methotrexate were found to be connected with the probability of relapse in the patients studied. The possible reasons for the prognostic role of systemic methotrexate clearance are discussed.

The effect of age on the pharmacokinetics of enoxacin.

We have studied the pharmacokinetics of enoxacin in two groups of subjects, 10 young (18-45 years) and 10 elderly adults (greater than 65 years) after a single oral dose of enoxacin (600 mg). Enoxacin was absorbed rapidly, peak plasma concentrations being reached within two hours in both groups. However, the peak plasma concentration of enoxacin was significantly higher in the elderly than in the young adults. The area under the concentration-time curve extrapolated to infinity was also significantly greater in the elderly compared with the young subjects, and the apparent renal clearance was significantly less in the elderly than in the young adults. Consequently, the urinary elimination of unchanged enoxacin was significantly reduced in the elderly. The apparent volume of distribution in the elderly was significantly less than in the young adults. The elimination half-time of enoxacin was similar in the two groups.

Toxicokinetics of inhaled 2-butoxyethanol (ethylene glycol monobutyl ether) in man.

Seven male volunteers were exposed to 2-butoxyethanol at the Swedish occupational exposure limit (20 ppm or 0.85 mmol/m3) during light physical exercise (50 W) on a bicycle ergometer. The exposure took place in an exposure chamber and lasted 2 h. Expired air was collected at regular time intervals for estimation of the respiratory uptake of the solvent. Arterialized capillary blood and urine were sampled during and after the exposure period and analyzed for 2-butoxyethanol and its metabolite butoxyacetic acid. A new sensitive method for analyzing 2-butoxyethanol in biological specimens is described. 2-Butoxyethanol was derivatized with pentafluorobenzoyl chloride and analyzed by gas chromatography with electron capture detection. The respiratory uptake of 2-butoxyethanol averaged 10.1 mumol/min or 57% of the inspired amount. The concentration in blood reached a plateau level of 7.4 mumol/l. The apparent values of elimination half-time, mean residence time, total blood clearance, and steady-state volume of distribution were 40 min, 42 min, 1.2 1/min and 54 l, respectively. The amount of 2-butoxyethanol excreted in urine was less than 0.03% of the total uptake, while that of butoxyacetic acid ranged from 17 to 55%.

Pharmacokinetic characteristics of the gonadotropin-releasing hormone analog D-Ser(TBU)-6EA-10luteinizing hormone-releasing hormone (buserelin) after subcutaneous and intranasal administration in children with central precocious puberty.

A double antibody RIA was developed for the measurement of the long-acting GnRH agonist D-Ser(TBU)6EA10GnRH (buserelin). The antibody, raised in rabbits against a buserelin-hemocyanin conjugate, reacted with the intact molecule and also molecular fragments containing the C6-9 tetrapeptide sequence and permitted the measurement of buserelin activity in serum and urine. Natural GnRH, LH, and FSH did not cross-react in this assay system. The assay was applied to samples obtained from children receiving buserelin for the management of central precocious puberty either by once daily injection of 30 micrograms/kg or by nasal spray (in; 200 micrograms every 8 h). Urine and serum samples, chromatographed on Sephadex G-25, contained immunoreactive material corresponding closely in molecular size to [125I]buserelin. In unextracted serum samples taken at intervals after sc therapy in 11 girls, the peak immunoreactive buserelin levels of 52.2 +/- 14.8 ng/ml (mean +/- SEM) occurred at 30 min. The half-time of elimination was 74.9 +/- 36.9 min. Approximately 30% of the dose was detected in urine collected for 3 h after injection. Similar data were obtained in 3 normal adults given 10 micrograms/kg buserelin, iv. By contrast, after the administration of 200 micrograms buserelin by metered nasal spray, the mean peak serum concentration in 10 girls was 100-fold less (0.65 +/- 0.14 ng/ml), although the halftime of elimination was almost identical. Only 0.73% of the nasal dose was excreted by 3 h. Calculated relative bioavailability data indicated maximal nasal absorption of 6%. However, absorption after nasal administration varied greatly, and in 2 children, serum and urinary concentrations of buserelin after supervised administration were negligible. We conclude that in buserelin therapy, in the dose used in this study, does not represent optimal treatment for the initial management of patients with precocious puberty. The success of in therapy in sustaining initial effects of buserelin given by sc administration presumably reflects changes in receptor sensitivity induced by sc treatment.

Thiopentalkinetik bei hochdosierter Anwendung

The kinetics of thiopentone when administered in high doses were investigated in two patients with elevated intracranial pressure and three patients with focal cerebral ischemia. Initial saturation of the tissues is best achieved by a series of infusions with decreasing infusion rate. Administration of a bolus followed by maintenance doses proved unsuitable. The course of concentration under maintenance dosage was extremely variable, mainly due to interindividual and intraindividual variations in clearance. The apparent distribution volumes in these patients (1.38-3.10 l/kg, mean 2.43 l/kg) corresponded to the volumes determined after bolus administration. The total body clearance was low (45.8-103.4 ml/min, mean 72.3 ml/min) and was the reason for long elimination half-times (15.6-25.0 h, mean 23.2 h). Four patients biotransformed thiopentone regardless of the concentration. In one female patient the biotransforming enzyme systems may have been saturated. While conversion of thiopentone to pentobarbitone is generally only of secondary importance, an unusually high plasma pentobarbitone concentration was observed in one patient, reaching 50% of the concentration of the original substance. On the average, thiopentone was 75-80% proteinbound. The binding rate changed considerably with time. It could not be shown that this was influenced by albumin concentration between 25 and 50 g/l. The thiopentone concentration in the ventricular fluid corresponded approximately to that in the plasma fluid. Owing to the variability of the total body clearance and plasma protein binding, and the possibility of changes in tolerance, thiopentone administration must be controlled individually according to the EEG and intracranial pressure. Monitoring of the drug concentration in plasma is recommended.

15-(ortho- 123I-phenyl)-pentadecanoic acid, a new myocardial imaging agent for clinical use

The result of previous experiments in rodents indicated different kinetics for the para- and ortho-isomers of 15-(iodophenyl)-pentadecanoic acid (p-IPPA, o-IPPA), with o-IPPA showing an enhanced rate of washout. To test the relevance of this phenomenon for clinical diagnosis, 15 fasting male patients with confirmed coronary heart disease (1-VD/7, 2-VD/4, 3-VD/4) were investigated under exercise. Serial images were recorded at a rate of 3 frames min-1 for 70 to 90 min, corrected for tracer in blood and compared with thallium-201 images obtained from these patients within less than 2 weeks. Time-activity curves were also taken from the peripheral blood. Ortho-IPPA was well taken up by healthy myocardium and, contrary to rodents, retained with elimination half times longer than 200 min. A decreased myocardial uptake was seen which was very similar to the pattern obtained with thallium. Ortho-IPPA was eliminated from the blood to less than 10% at 4 min. Almost all radioactivity was in the organic phase (greater than 95% at 5 min) and chromatography showed only one major peak (o-IPPA) indicative of minimal organic catabolism.

Myocardial fatty acid metabolism after acute ethanol consumption

This study was undertaken to assess the effect of ethanol ingestion on myocardial fatty acid metabolism in man. Nine individuals with informed consent and with a habitual ethanol consumption of approximately 40 g per day, but without any clinical signs of heart and metabolic disease, were examined after i.v. injection of omega-123I-heptadecanoic acid (IHA). Eight days later, these individuals were similarly examined after 2 h of continuous ingestion of a body weight dependent amount of ethanol, which was calculated to produce a blood level of 100 mg per 100 ml (1%). Then the subjects had been asked to reduce their ethanol consumption rigorously for 15 months. Subsequently after 2 weeks of abstinence a follow-up investigation without ethanol loading was carried out. The investigations were performed with an Anger scintillation camera in LAO-45 degrees projection. The measurement period was 40 min. Tracer accumulation and regional elimination half-times of IHA were analysed. In all patients, acute ethanol loading produced significant changes in pattern of accumulation and/or regional elimination half-times. Ethanol-induced alterations in segmental accumulation did not appear to be predictably correlated with changes in segmental elimination half-times. After rigorous reduction of ethanol consumption followed by 2 weeks of abstinence a normalization of the tracer uptake was observed; the distribution pattern was almost homogeneous. Also the regional elimination half-times became normal. The data demonstrate the significant effects of both chronic ethanol consumption and particularly acute ethanol loading on myocardial fatty acid metabolism and the reversibility of the effects.

Deposition, metabolism, and excretion of 1-[ 14C]nitropyrene and 1-[ 14C]nitropyrene coated on diesel exhaust particles as influenced by exposure concentration

Nitrated polycyclic aromatic hydrocarbons (nitro-PAH) have been detected in the environment, originating from sources such as diesel exhaust emissions and coal combustion fly ash. 1-Nitropyrene (NP) is a predominant mutagenic and carcinogenic nitro-PAH found in diesel exhaust emissions. Since inhalation of NP is a likely route of exposure in humans, it is important to determine the biological fate of inhaled NP both in its pure form and associated with particles. The purpose of this study was to determine the disposition of NP aerosols inhaled by rats. The studies described in this paper were designed to (1) determine the deposition of [ 14C]NP over a range of exposure concentrations, (2) identify the pathways and half-times for excretion of absorbed NP, and (3) determine the distribution of inhaled NP and metabolites in tissues. Male F344 rats were exposed nose only to various concentrations of NP and NP coated on diesel exhaust particles (50–1100 ng/liter). The results indicate that, over the range of concentrations tested, pathways for excretion of [ 14C]NP equivalents in urine and feces were independent of the exposure concentration of NP, whether in its pure form or associated with diesel exhaust particles. In all cases, fecal excretion was the major route of elimination of [ 14C]NP equivalents, with about 2 times more excreted by this route than by urine. The fractional deposition of [ 14C]NP in the respiratory tract did not appear to be dependent on exposure concentration. Half-times for elimination of 14C in urine and feces were about 15 to 20 hr. In all exposures. 14C was widely distributed in the tissues examined. Analysis of the tissues for NP and its metabolites indicated that within 1 hr after exposure, greater than 90% of the 14C was NP metabolites. Lungs of rats exposed to [ 14C]NP coated on diesel exhaust particles contained nearly 5 times more 14C than lungs from rats exposed to pure aerosols of [ 14C]NP (148 vs 29 pmol/g lung) within 1 hr after exposure. This difference was increased to 80-fold at 94 hr after exposure (80 vs 1 pmol/g lung). Long-term clearance half-times of 14C from various tissues were similar. The results demonstrate that particle association of NP significantly alters the biological fate of inhaled NP.

Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria.

Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg-1) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 +/- 0.27 l kg-1 (+/- s.d.), elimination half-time (t1/2,z), 11.3 +/- 4.3 h, total clearance, 1.22 +/- 0.77 ml min-1 kg-1. There was no relationship between arterial blood pressure and plasma quinine concentrations. Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg l-1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P less than 0.05). The mean (+/- s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 +/- 0.14. Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg l-1; simultaneous maternal plasma quinine was 7.1 mg l-1 (ratio 0.39). Breast milk quinine concentrations and milk to plasma ratios were 0.5-3.6 mg l-1 (mean 2.6) and 0.11-0.53 (mean 0.31) in twenty-five women who were breast-feeding and had taken oral quinine sulphate for 1-10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg l-1 (mean 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Sulfaphenazole in Sheep

Proprietary formulations of sulfaphenazole were administered intravenously and orally to sheep. After intravenous injection the disposition of sulfaphenazole was described by an open two compartment model, and the elimination half-time was on average 5.58 h. The apparent volume of distribution was 0.273 1/kg and total body clearance 34.1 ml/kg/h. Judged from the area under the curves, the oral dose was completely absorbed, Drug plasma concentrations versus time fitted an open one compartment model, the half-time of absorption and elimination being 2.66 and 7.12 h, respectively. The binding to plasma proteins was high i.e. 93–96 % at therapeutic concentrations, and concentration dependent. The results demonstrate that the doses indicated by the manufacturer appear to be low and more appropriate for drugs with a longer elimination half-time. Consequently, considerable adjustments in the dosage regimen are recommended.

Pharmacokinetics of fentanyl in patients undergoing abdominal aortic surgery.

The authors determined the pharmacokinetics of fentanyl 100 micrograms X kg-1 iv in patients undergoing elective abdominal aortic surgery. The mean (+/- SD) age of the ten patients was 67.2 +/- 8.7 yr; their mean weight was 78.5 +/- 13.7 kg. Seven patients had aortic aneurysm repair, and the other three patients had aortobifemoral grafts. Serum fentanyl concentrations were determined from samples drawn at increasing intervals over a 24-h period. A three-compartment pharmacokinetic model was fit to the concentration versus time data. Total drug clearance was 9.8 +/- 1.8 ml X min-1 X kg-1. The volume of distribution at steady-state (Vdss) was 5.4 +/- 1.9 X 1 kg-1. Elimination half-time was 8.7 +/- 2.5 h. There were no significant correlations between these pharmacokinetic parameters and patient's age, duration of aortic cross-clamping, duration of surgery, intraoperative blood loss, or volume of iv fluids given intraoperatively. In healthy volunteers or patients undergoing general surgery, other investigators report mean elimination half-times for fentanyl ranging from 1.7 to 4.4 h. The prolonged elimination half-time in patients having abdominal aortic surgery has important clinical implications. In particular, recovery from large doses will take much longer than would have been anticipated from previously published fentanyl pharmacokinetic data.

The distribution of mercury in the Indian population

Data have been obtained for the distributio of mercury in a non-occupationally exposed Indian adult group and compared with data available from other regions. The biological elimination half time for mercury of 33 days obtained here is in good agreement with the corresponding value for inorganic mercury compounds. The present work indicates that the relationship between dietary intake and blood concentration is only meaningful when long-term blood concentrations are measured.

Pharmacokinetics of TZU-0460, a new H2-receptor antagonist, in patients with impaired renal function.

We have studied pharmacokinetics of a new H2-receptor antagonist, TZU-0460, in patients with varying degrees of renal impairment. The apparent volume of distribution at steady-state was 1.70 l/kg, and the plasma protein binding of TZU-0460 or its active metabolite, desacetyl TZU-0460 was less than 10% in normal subjects. These variables were not altered with renal impairment. Sixty percent of TZU-0460 given orally was excreted via the kidney, mainly by tubular secretion. The half-time of elimination was 3.94 h in normal subjects, and was prolonged to 12.13 h in severe renal failure (creatinine clearance below 30 ml/min/1.48 m2). Dosage adjustment of TZU-0460 is necessary in renal failure.

Elimination of amino acids in acute renal failure.

Plasma amino acid concentrations and the elimination of parenterally administered amino acids were investigated in 12 patients with nonhypercatabolic acute renal failure. A distinctive plasma amino acid pattern could be observed: plasma concentrations of phenylalanine and methionine were increased, those of valine and leucine decreased. Of the nonessential amino acids, cystine, taurine und tyrosine had elevated but none of them reduced plasma concentrations. The elimination of amino acids was evaluated in a monocompartment model after bolus injection of an amino acid solution containing essential and nonessential amino acids. Pharmacokinetic parameters of 17 amino acids were calculated. The mean elimination half-time was raised by 25%. The elimination half-time of phenylalanine, methionine, glutamic acid, proline and ornithine was increased. Histidine was the only amino acid with--however insignificantly--accelerated elimination from the intravascular compartment. The total clearance rate and total transfer rate was not altered (107 and 97% of normal, respectively). The clearance of threonine, lysine, serine, glycine and histidine was increased, of valine, phenylalanine, glutamic acid and to a minor degree of methionine was decreased. The transfer rate of methionine, lysine, glycine was elevated, of valine, aspartic acid, glutamic acid and ornithine reduced. The demonstration of these pronounced alterations of amino acid elimination in acute renal failure may have major consequences in parenteral amino acid therapy.

Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients

The pharmacokinetics of azathioprine (AZA) and 6-mercaptopurine (6-MP) was studied in uremic patients after 100 mg AZA intravenously (fifteen patients) and orally (eight patients). 6-MP was analysed with gas chromatography mass spectrometry following extractive alkylation. AZA was determined indirectly assuming quantitative conversion to 6-MP in whole blood. The plasma concentration of AZA fell rapidly after i.v. administration. The mean half-time of elimination for the first rapid phase ( t 1 2 α was 6.1 min (S.D. ± 4.1) and for the terminal phase ( t 1 2 β ) 50 min (± 31). The total plasma clearance (C1) was 6.91./min (± 3.0). AZA was rapidly converted to 6-MP in vitro, and maximal plasma concentrations of 6-MP were found as early as 5 min after i.v. injection of AZA. The mean t 1 2 α was 4.6 min (± 2.2), t 1 2 β 74 min (± 58) and C1 8.01/min (± 5.8). The plasma levels of both AZA and 6-MP were either low or undetectable 4–6 h after dose. In erythrocytes AZA levels were low or undetectable indicating rapid conversion to 6-MP in these cells. 6-MP concentration - time curve in erythrocytes was similar to that in plasma, except for a somewhat slower terminal phase of elimination. Oral administration of AZA generated flat plasma curves for AZA and 6-MP. The area under the concentration - time curve (AUC) was considerably smaller than after i.v. administration, 18 and 41% for AZA and 6-MP, respectively. There seems to be little danger of accumulation of AZA/6-MP in uremia. We also studied inhibition of Leucoagglutin (LA) stimulated lymphocyte proliferation by patient plasma at different times in six of the patients following AZA i.v. Sera drawn at 5, 10 and 30 min significantly inhibited the LA-induced proliferation, with an estimated minimum effective concentration of 6-MP in the cultures of about 0.02–0.04 μM. This suggests the possibility of a therapeutic effect even of the low plasma levels of 6-MP obtained after AZA orally. The combined use of sensitive pharmacokinetic and immunological assays as described should be useful in studying the relationship between plasma levels of AZA/6-MP and their immunosuppressive effect and toxicity.