Rate of elimination of tracer doses of phenytoin at different steady-state serum phenytoin concentrations in epileptic patients

1 Serum phenytoin concentration, the serum half-life of a tracer dose of carbon-labelled phenytoin, and the ratio of the major metabolite of phenytoin to unchanged drug in urine (p-HPPH: DPH ratio) were measured in epileptic patients on chronic anticonvulsant therapy.

2 A significant correlation was found between serum phenytoin concentration and half-life, the slope of the regression line being dose dependent.

3 A significant negative correlation was found between serum phenytoin concentration and p-HPPH: DPH ratio.

4 Increasing the daily dose of phenytoin lead to a lengthening of the half-life and a reduction in the p-HPPH: DPH ratio. The reverse occurred on lowering the dose.

5 These changes indicate that phenytoin hydroxylation is saturable.

6 Difficulty in achieving a stable serum phenytoin concentration within the therapeutic range may result.

     

The relationship of plasma chlorpromazine to its 7-hydroxy and sulphoxide metabolites in a large population of chronic schizophrenics

1 Blood samples were obtained from eighty-six chronic schizophrenics receiving a wide range of oral doses of chlorpromazine. Plasma concentrations of chlorpromazine, 7-hydroxychlorpromazine and chlorpromazine sulphoxide were estimated using a sensitive gas-liquid chromatographic method and their relationships to oral dose and to global clinical control were investigated.

2 Wide variability was observed in the plasma concentrations of unchanged drug and metabolites between patients receiving similar daily doses.

3 In general the plasma concentrations of the 7-hydroxy and sulphoxide metabolites were of similar magnitude to the concentrations of chlorpromazine.

4 Global symptom control was unrelated to the plasma concentration of unchanged chlorpromazine. However, patients judged to be under good control had relatively higher concentrations of the biologically active 7-hydroxy metabolite in their plasma than patients who were poorly controlled and in whom the biologically inactive sulphoxide metabolite predominated. When the ratio of 7-hydroxychlorpromazine to chlorpromazine sulphoxide was derived for each patient, a highly significant difference was found to exist between the metabolite ratios of patients grouped according to clinical control.

5 It is suggested that a prediction of therapeutic response to chlorpromazine may be provided in the form of the ratio of the plasma concentration of biologically active metabolite to the concentration of either the unchanged drug or its inactive metabolite.

     

Inhibition of phenytoin metabolism by sulthiame in epileptic patients

1 Measurements have been made of steady state serum phenytoin concentration, serum half-life of ¹⁴C-labelled phenytoin, and the urinary ratio of the major metabolite of phenytoin to the unchanged drug (p-HPPH: DPH ratio) in epileptic patients on and off sulthiame therapy.

2 Starting sulthiame treatment produced an increase in serum phenytoin concentration, a prolongation of the half-life and an increase in the p-HPPH: DPH ratio. The total urinary output of phenytoin plus p-HPPH was unaltered by sulthiame.

3 The results indicate that sulthiame or one of its metabolites inhibits the parahydroxylation of phenytoin by hepatic enzymes.

     

Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose

1 The plasma pharmacokinetics of metronidazole following a single dose (500 mg) of metronidazole have been investigated in a crossover study in healthy female volunteers, using assays specific for metronidazole and its metabolites 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (metabolite I) and 2-methyl-5-nitroimidazole-1-acetic acid (metabolite II).

2 No systematic differences, which could be related to the route of metronidazole administration, were observed in the area under the plasma metronidazole concentration against time curve, elimination half-life, apparent volume of distribution, or total urinary excretion of metronidazole. Following a single oral or intravenous dose, the half-life estimates were 7.0 h and 7.3 h respectively.

3 No metabolite II was detected in plasma following the administration of metronidazole by either route. Urinary elimination of this metabolite appeared to be independent of the route of administration.

4 No systematic differences, which could be related to the route of administration, were observed in the apparent half-life or total urinary excretion of metabolite I. However, the area under the plasma concentration against time curve for metabolite I was significantly greater (+27%) following oral administration than following intravenous administration.

5 A single dose of metronidazole (500 mg) produced a peak plasma concentration for the drug which was in excess of the minimum inhibitory concentration of most susceptible anaerobic bacteria, and in several of the volunteers such an inhibitory concentration of metronidazole was maintained in plasma for more than 8 h following a single dose.

     

Acetylation of procaine amide in man studied with a new gas chromatographic method

1 A specific gas-chromatographic method was developed for determination of N-acetylprocaine amide in plasma and urine, using 4-amino-N-(2-piperidinoethyl)benzamide as an internal standard. The investigation was performed in 50 cardiac patients who had reached steady-state plasma concentrations of procaine amide.

2 The plasma concentrations of the acetylated metabolite varied between 1.0 and 15.0 μg/ml and were thus of the same order of magnitude as those of the parent drug. Especially high plasma levels of the metabolite were seen in patients with poor kidney function.

3 The urinary excretion of the metabolite varied markedly between individuals and ranged between 6 and 52% of the administered daily dose. There was a clear tendency towards higher rates of acetylation of procaine amide in patients with short plasma half-lives of isoniazid, i.e. the phenotype rapid acetylators. Because of coexisting therapy with other drugs and impaired renal function in some patients studies are required in healthy human volunteers to ascertain whether the acetylation of procaine amide and isoniazid are mediated by the same enzyme system.

     

A preliminary study of the effect of norfenfluramine on lipogenesis by human adipose tissue in vitro

1 Norfenfluramine is thought to be the major active metabolite of fenfluramine in man. Therefore its in vitro effect on lipogenesis in human adipose tissue from twelve patients was investigated.

2 Although inhibition of lipogenesis was demonstrated, the concentrations of norfenfluramine necessary (>1 mM) were much higher than normal blood levels of the drug.

3 There was no correlation between the degree of inhibition by norfenfluramine in vitro and fat cell size, age or relative weight of the subject. Greater degrees of inhibition were however associated with samples of tissue from patients with higher blood glycerol concentrations and lower blood triglyceride concentrations.

     

Metabolism and distribution of exogenous histamine in cats

1 The metabolism and disposition in blood and tissues of exogenous [¹⁴C]-histamine was examined in cats.

2 The principal metabolites in blood of histamine instilled into the small intestine (directly or by transfer from the stomach) and colon were imidazoleacetic acid and t-methylimidazoleacetic acid, being present in approximately equal amounts although in individual cats one or other acid could predominate. Only small amounts of histamine entered the circulation although in two of four cats given the largest dose (82 μmol/kg) large amounts were recovered. The amount of ¹⁴C radioactivity absorbed varied directly with the dose instilled. The chief metabolite in kidney and urine, whether histamine was instilled into the intestine or infused parenterally, was t-methylimidazoleacetic acid. Histamine was not absorbed from the stomach and its metabolism there was negligible.

3 In contrast, when histamine was infused into blood leaving the intestine (portal vein) the main metabolite in blood and tissues was t-methylimidazoleacetic acid being found in approximately 5-fold the concentration of imidazoleacetic acid. The small amount of histamine which eluded inactivation/uptake by liver, lungs, heart during the infusion was halved on circulation through the intestine. When histamine was infused into blood supplying the intestine, (cranial mesenteric artery) t-methylimidazoleacetic acid while still the major metabolite in blood was now only 1.4 times the concentration of imidazoleacetic acid. Additionally, the blood concentration of histamine during the infusion exceeded that of the metabolites.

4 t-Methylimidazoleacetic acid was also the principal metabolite in blood and tissues following histamine infusion into a cannula carrying a replacement venous blood supply to the liver of abdominally eviscerated cats. Imidazoleacetic acid and t-methylhistamine were present in equal concentrations and in one-quarter to one-third that of the methylated acid. The latter was also the principal metabolite following intra-arterial histamine infusion to abdominally eviscerated cats without a hepatic blood supply, although initially t-methylhistamine predominated: a large peak of histamine was present during the infusion period. When additionally the renal vessels were ligated, t-methylhistamine predominated throughout the experiment.

5 In conclusion, intraduodenally instilled histamine was metabolized equally by diamine oxidase and imidazole N-methyltransferase (followed by deamination by monoamine oxidase). In contrast, imidazole N-methyltransferase was the principal inactivator of parenterally infused histamine, deamination of t-methylhistamine by monoamine oxidase becoming progressively less efficient with the cumulative exclusion of the intestines, liver and kidney from the circulation.

     

Phenytoin dose adjustment in epileptic patients

1 A preliminary survey showed that many outpatients with partially controlled epilepsy had serum concentrations of phenytoin below the recommended therapeutic range (10-20 μg/ml). A phenytoin tolerance test was devised with the intention of predicting a more adequate daily dose for such a patient.

2 Fifteen patients were each given an oral test dose of 600 mg phenytoin sodium and the serum concentration of phenytoin was measured at intervals over 48 h; the concentration rose during the first 4 h and decayed between 12-48 h as an almost linear function of time.

3 The serum concentration/time curves were fitted by an interative computer program based on the Michaelis-Menten equation. The mean saturated rate of elimination of phenytoin was 435 mg/day and the serum concentration (K_m) corresponding with 50% saturation was 3.8 μg/ml. The mean calculated dose of phenytoin sodium required for a steady state serum concentration of 10-20 μg/ml was 345-400 mg/day.

4 The Michaelis-Menten principle was used to predict steady state serum phenytoin concentrations in individual patients receiving daily doses of phenytoin sodium adjusted by steps of 100 mg. The serum concentrations tended to be either too low or too high. The steep relationship between phenytoin concentration and dose indicates that when the concentration reaches 5-10 μg/ml it is then appropriate to adjust dose by small steps of about 25 mg.

     

Accumulation of debrisoquine by platelets in vivo: A model of events at the peripheral adrenergic neurone?

1 The possibility that in vivo uptake of D by human platelets might reflect its accumulation in the post-ganglionic adrenergic neurone, and hence be a useful predictor of hypotensive response, was investigated.

2 During chronic oral dosage of D in three hypertensive patients average concentrations of the drug in blood fractions relative to plasma were: platelet rich plasma, 2.93; whole blood, 2.23; red cells plus granulocytes, 0.75. These findings indicate extensive uptake of D by platelets but not by other cells.

3 After single oral doses of 30 mg debrisoquine to four healthy volunteers platelets continued to accumulate the drug over at least 24 h. Although platelet D concentrations varied between subjects their platelet/plasma drug concentration ratios were similar.

4 Amitriptyline (75 mg p.o.) given 2 h before a single 30 mg oral dose of D inhibited platelet uptake of the latter by 40 ± 14 s.d.% over a 24 h period.

5 Platelets accumulated D but not its inactive 4-hydroxy metabolite. During chronic dosage of D in 10 patients the mean pre-dose platelet/plasma D concentration ratio was 8.52 ± 429 s.d. Within a 12 h dosing interval the concentration of D was constant in platelets but varied two-fold in plasma.

6 Uptake of D by platelets approached saturation with increasing plasma D concentrations.

7 After chronic D therapy in patients the fall in standing diastolic bp was more closely correlated with plasma D concentration (r = -0.88; P < 0.001) than with platelet D concentration (r = -0.65; P < 0.05).

8 In relation to the therapeutic response to D, observations 3-5 but not 7 are consistent with a view of the platelet as a useful model of the peripheral adrenergic neurone.

     

Digoxin prescribing in perspective

1 Prescribing aids based on creatinine clearance were evaluated in 86 out-patients taking digoxin at a district general hospital. Lanoxin tablets were dispensed in calendar packs to encourage patient compliance.

2 Despite a high degree of patient compliance and a more than three-fold variation in creatinine clearance the range of concentrations that would result from prescribing individual doses based on creatinine clearance was similar to that expected from prescribing one fixed dose for all male and another for all female patients.

3 Concentrations at which symptoms of toxicity occurred in 31 patients did not differ significantly from concentrations achieved in the remainder.

4 Only 17% of the variance in resting ventricular rate in patients with atrial fibrillation and no serious impairment of atrio-ventricular conduction was explained by the serum digoxin concentration.

5 Even when the serum digoxin concentration is known the patient's clinical condition must be the final determinant of dose.

6 Patients with symptoms of toxicity were distinguished by significantly lower serum creatinine concentrations and body weights, factors suggestive of a lower muscle mass. No other biochemical or clinical (other than serum digoxin concentration) factors influencing resting ventricular rate in atrial fibrillation were identified.

     

Prescribing aids for gentamicin

1 A nomogram and a digital computer program have been developed to calculate dosage schedules of gentamicin for individual patients. The minimum input data consist of the patients' age, sex, body weight and serum creatinine concentration.

2 These prescribing aids have been evaluated in 36 patients with severe Gram negative infections. Renal function ranged from normal to complete anuria. Nomogram dosage schedules gave serum concentrations of gentamicin within the chosen therapeutic limits. Physician dosage schedules gave serum concentrations which sometimes exceeded and sometimes fell below these limits. The validity of the computer program was demonstrated by its ability to predict serum concentrations of gentamicin whatever the dosage schedule.

3 Half the patients recovered from the bacterial infection but seven remained infected and eleven died. Pseudomonas aeruginosa was the most difficult organism to eradicate.

4 Four of the patients who survived developed ataxia and two developed hearing loss at high frequencies. The risk of ototoxicity was a function of mean trough serum gentamicin concentration and duration of treatment. Ototoxicity was only detected in patients with serum creatinine concentrations above 3 mg/100 ml who tended to have higher trough concentrations. When treatment was prolonged beyond 8-10 days the risk of ototoxicity was increased without evidence of further substantial therapeutic benefit.

     

Concentration-effect relationships with FM 24: A new long acting β-adrenergic receptor antagonist

1 FM 24, 1-(2-exo-bicyclo[2,2,1] hept-2-tl phenoxy-3[(1-methyl/ethyl) amino]-2-propanol is a new β-adrenoceptor antagonist. The drug-receptor complex dissociates very slowly in vitro, probably because of the rigidity of the norbornyl ring (Le Fur et al., 1978).

2 Five healthy male volunteers were given single oral doses of placebo, 20, 40, 80, 160 and 320 mg of FM 24. Two hours later a sub-maximal exercise test was carried out with measurement of heart rate and blood pressure and a blood sample was taken for measurement of the plasma concentration of FM 24. Progressive inhibition of exercise tachycardia was observed, related approximately linearly to the log concentration of the drug. At the 320 mg dose a high degree of inhibition of exercise tachycardia occurred with a maximum heart rate of 115 beats min^-1.

3 Five healthy volunteers were then given a single oral dose of 80 mg and 320 mg of FM 24 on separate occasions. Blood samples were taken and submaximal exercise tests were carried out before and at 2, 6, 12, 24, 36, 60, 108 and 168 h after the dose. The plasma concentration fell rapidly during the first 24 h and by that time was less than 10% of the peak value. The degree of inhibition of submaximal exercise tachycardia changed little during the first 24 h after the dose and thereafter declined at a rate which varied in different subjects.

4 The main interest of the study lies in the difference in the concentration-effect relationship 2 h after doses of 20-320 mg and over 7 days after 80 mg or 320 mg doses. At 2 h there was an approximately linear relationship between log FM 24 concentration and inhibition of exercise tachycardia. In the 7 day study the inhibition of exercise tachycardia was on a plateau for the 6-24 h period. During this time the plasma concentration fell rapidly. The data are consistent with a prolonged duration of action due to a slow dissociation of the drug receptor complex, although an active metabolite of FM 24 cannot be excluded. The plateau of effect during the 6-24 h period is of particular interest. One possible explanation is that it represents the turnover time of the cardiac β-adrenoceptors.

     

Biotransformation and excretion of lorazepam in patients with chronic renal failure

1 To evaluate the effect of end-stage renal insufficiency and haemodialysis on the elimination of lorazepam, single oral doses of the drug (2.5 mg) were administered to normal subjects and patients with chronic renal failure (CCr: less than 2 ml/min) in the interdialysis period and during haemodialysis.

2 The concentration of lorazepam and its major metabolite, lorazepam-glucuronide, were assayed using electron capture g.l.c.

3 Plasma half-life (T_½) of unchanged lorazepam in the patient group (11.3 ± 0.6 h) was not different from that obtained in normals (11.1 ± 0.9 h).

4 Only minor quantities of the unchanged drug could be recovered in the 24 h urine in both groups: 0.3% of the ingested dose in normals and trace amounts in the patient group.

5 No unchanged lorazepam could be detected in the ultrafiltrate from the coil kidney. Since the lower sensitivity of the method is about 5 ng/ml, this would indicate the in vivo binding of the active drug to plasma proteins to be at least 70%.

6 The effect of haemodialysis on lorazepam plasma T_½ was also insignificant (9.4 ± 1.0 h).

7 Urinary excretion of lorazepam-glucuronide was found to be considerably decreased in chronic renal failure associated with accumulation of high concentrations of this conjugate in plasma during days after a single oral dose. The plasma T_½ of this conjugate in normals was 20.7 ± 2.1 h.

8 Roughly 35% of this main metabolite's concentration in plasma was detected in the ultrafiltrate from the coil kidney indicating the dialyzability of this conjugate and that the extent of plasma protein binding of lorazepam-glucuronide in vivo was approximately 65%.

9 The above results indicate that after a single oral dose (2.5 mg) the biotransformation of lorazepam to its glucuronide conjugate remains unaltered and that high concentrations of this metabolite accumulate in plasma in the presence of severe renal function impairment.

     

Effect of heparin on serum binding of propranolol in the acute phase of myocardial infarction

1 Binding of propranolol in vitro was determined in sera from 38 non-fasting patients 4-6 days after an acute myocardial infarction. The binding of propranolol was significantly lower in 12 patients receiving a subcutaneous heparin injection than in 26 patients receiving warfarin.

2 The binding of propranolol in sera from 9 geriatric patients without any acute diseases and 10 young, healthy subjects was similar to that of patients with acute myocardial infarction receiving heparin.

3 Mean serum concentration of α₁-acid glycoprotein was similar in the four different groups of individuals.

4 For all subjects, the binding of propranolol was positively correlated to serum concentrations of α₁-acid glycoprotein.

5 In the patients with myocardial infarction the binding was negatively correlated to serum concentrations of non-esterified fatty acids. Mean serum concentrations of non-esterified fatty acids was significantly higher in the patients receiving heparin than those receiving warfarin.

6 Addition of heparin and palmitic acid to serum in vitro did not affect the binding of propranolol.

7 The effect of heparin on binding variations was observed more closely in three non-fasting patients with myocardial infarction. Serum binding of propranolol and concentrations of chylomicrons and pre-β-lipoproteins were significantly reduced after a subcutaneous heparin injection of 5,000 iu, while serum concentrations of non-esterified fatty acids increased threefold. Concentrations of α₁-acid glycoprotein and albumin were unchanged. Changes in binding of propranolol was closely correlated to concomitant changes in the triglyceride-rich lipoproteins.

8 These observations indicate that propranolol is bound to both triglyceride-rich lipoproteins and α₁-acid glycoprotein in serum. Even smaller doses of heparin activate lipoprotein lipase and decrease binding of propranolol to lipoproteins in non-fasting subjects.

     

Effects of a combined oestrogen-progestin preparation on gastric acid and pepsin secretion, serum gastrin concentration and biliary secretion of bile acids, phospholipids, and cholesterol in the cat

1 Daily ethinyloestradiol (50 μg) and norethisterone acetate (1 mg) treatment (Minovlar) was investigated on gastric acid and pepsin secretion, and fasting serum gastrin concentration in six conscious female cats prepared with chronic gastric fistulae. The effect on biliary secretion of bile acids, phospholipids, and cholesterol was investigated in three conscious female cats prepared with chronic gastric and intestinal fistulae, and cholecystectomy.

2 Treatment for 49 days did not alter the gastric acid or pepsin response to either intravenous pentagastrin infusions or a food stimulus. The fasting serum gastrin concentration remained unaltered throughout the study.

3 Treatment for 18 days did not alter the percentage concentration of cholesterol in the bile, but reduced the percentage concentration of phospholipid. This was mirrored by a rise in the percentage concentration of bile acids in the bile. These trends were quickly reversed on cessation of treatment.

4 There was no sign of cholestasis associated with the treatment. Intestinal flow remained constant throughout the study, there was no lithocholic acid or other abnormal bile acids detectable in any samples, and there was no change in serum aspartate aminotransferase concentration.

5 The results suggest that in female cats, treatment with a combined oestrogen-progestin preparation does not exert any beneficial effects on the aetiology of peptic ulceration through the reduction of acid or pepsin secretion, or the lowering of serum gastrin concentration. The preparation shows a tendency to produce more lithogenic bile, and this may partly explain the greater incidence of gall stones in women on the contraceptive pill.

     

Influence of intrinsic sympathomimetic activity of β-adrenoceptor blockers on the heart rate and blood pressure responses to graded exercise

1 The relationship between plasma concentration and effect on heart rate and blood pressure at rest and at three levels of exercise were examined for four β-adrenoceptor blocking drugs having differing pharmacological properties.

2 Four doses of each drug were administered, the highest doses producing maximum effects of the work-heart rate and work-blood pressure relationships.

3 Pindolol and oxprenolol, which have intrinsic sympathomimetic activity (ISA) differed from timolol and metoprolol (which do not) in having a smaller effect on resting heart rate at each dose.

4 During exercise the four drugs had similar maximum effects on slope of the work-heart rate relationship suggesting similar suppression of reflex enhancement of sympathetic activity during exercise by each drug. The higher heart rate after drugs with ISA at rest was therefore still present at each level of exercise, e.g. maximum reduction of heart rate at 0.5 maximum work capacity was 20.5, 20.8. 24 and 28% for pindolol, oxprenolol, metoprolol and timolol respectively (P < 0.01 for difference between drugs with and without ISA).

5 The relationship between plasma concentration and reduction of heart rate at 0.5 maximum work capacity was qualitatively similar for each drug and was adequately described by a sigmoidal relationship wtih half-maximal effects at 4.4, 22, 35 and 5 ng/ml for pindolol, oxprenolol, metoprolol and timolol respectively whilst maximal effects occurred at approximately 30, 150, 100 and 30 ng/ml.

6 The results suggest that differences with exercise heart rate due to ISA are mainly due to effects on resting heart rate. The dose-response relationship of β-adrenoceptor blockers reaches a plateau at higher doses, irrespective of whether or not they possess ISA.

     

A controlled trial of practolol in mild hypertension

1 Fifteen patients with diastolic blood pressures between 90 and 120 mmHg were admitted to a trial comparing placebo with practolol at doses up to 500 mg 12 hourly.

2 The trial was a double blind cross over study. Treatments were allocated at random and each treatment block lasted 12 weeks.

3 Ten patients completed the trial, and none of those who withdrew experienced serious unwanted effects.

4 Practolol caused significant falls in standing systolic and diastolic pressures and the supine diastolic pressure.

     

The pharmacokinetics of methimazole after oral administration of carbimazole and methimazole, in hyperthyroid patients.

1 Methimazole plasma concentrations were measured in two groups of hyperthyroid subjects after the oral administration of either carbimazole or methimazole. 2 With the HPLC method it was also possible to measure the concentration of a methimazole metabolite, 3-methyl-2-thiohydantoin in one patient. 3 Large interindividual differences were observed, especially within the carbimazole group. 4 Incomplete absorption of carbimazole could explain particular high apparent volumes of distribution and apparent clearances.     

A controlled study on the antihypertensive effect of a new beta-adrenergic receptor blocking drug, metoprolol, in combination with chlorthalidone

1. A double-blind crossover evaluation of the antihypertensive effect of metoprolol v. placebo was carried out in a series of twenty-three patients with mild or moderate essential hypertension who were receiving chlorthalidone (25 mg daily) as their basic treatment. An individually titrated metoprolol dosage (75-300 mg) was used. The double-blind crossover study consisted of two 3-month periods during which the patients received either metoprolol or placebo in addition to chlorthalidone.

2 Metoprolol, as compared with placebo, produced a statistically significant reduction of blood pressure, both in supine and standing positions. Normotension was achieved during metoprolol-chlorthalidone treatment in twenty-two of the twenty-three patients, but during placebo-chlorthalidone treatment in only twelve of the twenty-three patients.

3 During the double-blind crossover study mild side-effects occurred during metoprolol-chlorthalidone treatment in fourteen patients during first month, in twelve patients during second month and seven patients during third month. During placebo-chlorthalidone treatment side effects occurred in seven, six and seven patients, respectively.

4 In conclusion, metoprolol caused a significant fall in blood pressure when given to patients already receiving chlorthalidone. Metoprolol in combination with chlorthalidone appears to be an effective and well-tolerated treatment for mild and moderate hypertension in those patients not responding to chlorthalidone alone.

     

Placental transfer of pyridostigmine in the rat

1. Carbon-14 labelled pyridostigmine in single doses was given by intramuscular injection to pregnant rats, and maternal blood, foetal and placental homogenates were examined for total radioactive content, pyridostigmine and its metabolite, 3-hydroxy-N-methyl pyridinium.

2. The level of radioactivity in all tissues was highest at 15 min and fell to negligible amounts at 24 hr. The concentrations in placenta were similar to those in maternal blood, but there was some indication of retention of radioactive drug in the placenta. The concentrations in the foetus were substantially lower, but the subsequent slow decline in concentration suggests that cumulation of the drug could occur with repeated doses.

3. The percentage of metabolite in the foetus was considerably higher than in placenta and blood, and the possible reasons for this are discussed.