I. H. Stevenson

Impairment of human drug metabolism by oral contraceptive steroids.

The effect of oral contraceptive steroids on drug‐metabolizing capacity was determined by the use of plasma antipyrine and phenylbutazone half‐lifes as indices. Drug‐metabolizing capacity seemed to be impaired in women taking oral contraceptive steroids since the mean plasma antipyrine half‐life in female control subjects was 10.8 ± 2.4 hours (N = 36) while that in the “pill” group was 14.1 ± 3.1 hours (N = 26). The difference between the groups was significant (p < 0.001). With phenylbutazone, the mean control value was 70.6 ± 30.1 hours (N = 18) and that for the subjects taking oral contraceptives 80.2 ± 30.6 hours (N = 18). In this case the difference was not statistically significant (p > 0.05).

Hepatic drug-metabolising enzyme activity and duration of hexobarbitone anaesthesia in barbitone-dependent and withdrawn rats

Abstract The activity of several hepatic drug-metabolising enzymes and the duration of hexobarbitone anaesthesia were determined in barbitone-dependent and withdrawn rats. Rats were made dependent on barbitone sodium by the administration of increasing amounts in the drinking water over a 32-day period. Abrupt withdrawal was accompanied by a characteristic withdrawal syndrome. The body weight, liver weight and body weight/liver weight ratio were found to be increased during barbitone treatment and to fall after withdrawal. The liver protein and glycogen content did not change during barbitone treatment. Withdrawal produced a transient reduction in hepatic glycogen content but did not affect protein levels. The capacity of hepatic microsomal preparations to metabolise hexobarbitone, aminopyrine and prontosil and to conjugate o -aminophenol was increased by barbitone treatment. Following withdrawal, the enzyme activity fell below that of control animals Four months after withdrawal the liver enzyme activity was still subnormal. The acute administration of phenobarbitone to 4-month withdrawn animals was found to restimulate hepatic microsomal drug-metabolising enzymes but the level attained was not as high as that found in phenobarbitone-treated control rats. The same degree of tolerance to injected hexobarbitone, as indicated by reduction in sleeping time, was found at all stages of barbitone treatment. A hypersensitivity to hexobarbitone was produced by withdrawal. It is concluded that both the tolerance in barbitone-dependent rats and the hypersensitivity of withdrawn animals can be adequately explained by altered hepatic drug-metabolising enzyme activity.

Stimulation of drug metabolism in man by tricyclic antidepressants

SummaryPlasma antipyrine half-lives were measured in thirty adult subjects before and after 7 and 28 days treatment with one of five tricyclic antidepressants. Overall, considering the five antidepressants together, there was a small but significant reduction in half-life after both periods of treatment. In four subjects studied, increased urinary output of 6β-hydroxycortisol following chronic nortriptyline treatment provides further evidence of a stimulatory effect of tricyclic antidepressant on drug metabolism. In a separate study, the induction effect of tricyclic antidepressants was found to be much less marked than that with amylobarbitone. It would seem therefore that tricyclic antidepressants are less likely than barbiturates, to bring about drug interactions by altering drug metabolism.

Patterns of drug prescribing for children in hospital.

SummaryThe drugs prescribed for children in Tayside hospitals in 1974 and 1975 were surveyed using the computer files of over 4000 children in each year. The results were compared with similar data on adult patients. Although similar proportions of both age groups received drugs, less than 3 drugs were prescribed for the great majority of the children (mean 2.5) compared with twice that number for adults.Seven classes of drugs accounted for almost four-fifths of the drugs prescribed for children but the same classes formed two-fifths only of the total drug use in adults. There was significantly greater use of antihistamine/sedative, anticonvulsant and decongestant/mucolytic drugs in children than in adults while the reverse was true for diuretics, KCl, cardioactive agents, sedatives/hypnotics, and tranquillisers.Antimicrobial drugs accounted for approximately one-third of the total drugs used in children and one half of all patients received at least one drug from this class. Penicillin preparations alone accounted for 65.1 per cent of all antimicrobial drug use. The percentage of children given ampicillin fell by almost half from 1974 to 1975 with a corresponding increase in the proportion receiving amoxycillin.

Altered Plasma Protein Binding of Drugs in Thyroid Disease

The plasma protein binding of propranolol and warfarin was studied in vitro by ultrafiltration in hyper- and hypothyroid patients both before and after treatment. The degree of binding of propranolol was significantly decreased in hyperthyroid patients and increased in hypothyroid patients, and was negatively correlated with serum thyroxine and the free thyroxine index. The plasma protein binding of warfarin was also decreased in hyperthyroid patients, but was unchanged in hypothyroid patients. These results suggest that the binding of both acidic and basic drugs may be altered by thyroid disease.

Increased Clearance of Propranolol in Thyrotoxicosis

The pharmacokinetics of oral propranolol were studied during chronic treatment in six patients when thyrotoxic and again when euthyroid. The mean total plasma propranolol steady-state concentration was 42% lower when the patients were thyrotoxic. After treatment of thyrotoxicosis there was a fall (P less than 0.05) in the oral clearance of both total (4.2 +/- 0.6 to 2.7 +/- 0.4 L/min, mean +/- SEM) and free (30.5 +/- 4.7 to 25.5 +/- 4.1 L/min) propranolol although the half-life of propranolol did not change significantly. The free fraction of propranolol was higher (p less than 0.05) in the thyrotoxic (14.2% +/- 1.3%) than in the euthyroid (11.4% +/- 0.8%) state. These results suggest that the pharmacokinetics of propranolol are significantly altered in thyrotoxicosis.

Propranolol dynamics in thyrotoxicosis

Twenty‐five thyrotoxic patients were treated with propranolol (160 mg/day) for 1 to 2 wk. Although the response to therapy varied there was a reduction (p < 0.001) in supine and exercise heart rates and in sitting pulse rate. Serum triiodothyronine (T3) fell (p < 0.001) and serum thyroxine did not change during propranolol therapy. Plasma propranolol levels before assessment varied from 5 to 121 ng/ml, and there were positive correlations between them and percentage reduction in exercise (r = 0.78, p < 0.001) and resting (r = 0.61, n = 14, p < 0.05) heart rates, percentage reduction in sitting pulse rate (r = 0.73, p < 0.001), and the percentage reduction in serum T3 (r = 0.59, n = 23, p < 0.01). Although weight loss ceased in the group as a whole the degree of continued weight loss or weight gain in individual patients was also related to plasma propranolol concentration (r = 0.61, p < 0.01). The plasma propranolol level correlated (r = 0.62, p < 0.01) with thyrotoxicosis therapeutic index. There was no correlation between degree of subjective improvement and plasma propranolol level.

The effect of immunization with digoxin-specific antibodies on digoxin disposition in the mouse

After intravenous dosing, digoxin was rapidly distributed to tissues, with a distribution half-life of 3.0 min. The highest digoxin concentrations at 1 hr post dosing were found in lymph nodes, adrenals, gallbladder (including contents), liver and kidney respectively. Digoxin concentrations in the heart, spleen, brain, lung, skeletal muscle and fat were similar to, or lower than, those in the plasma. The apparent volume of distribution (AVd) was 1 l/kg, and the plasma elimination half-life and clearance (Cl) 2.8 hr and 0.25 l/kg per hr respectively. When digoxin was given one day after passive immunization with digoxin-specific immunoglobulin G (IgG) or Fab fragments the respective plasma digoxin concentrations were elevated some 26- and 5-fold respectively compared with control values. Consequently there were reductions in AVd (93 and 32%) and Cl (94 and 50%). The effect of IgG treatment on clearance was still apparent when the hapten was given up to 14 days after immunization, while the weaker effect of Fab-treatment was less persistent. Although tissue digoxin concentrations were slightly lower in the immunised mice, it was only in the lymph nodes at 10 and 14 days after IgG treatment that the reduction in hapten concentration was statistically significant.

The effect of chlorpromazine on drug metabolism

Curry, Lader & others (1971) have demonstrated a lowering of the steady-state plasma level of chlorpromazine, beginning two weeks after the start of treatment with a constant dose of drug. They suggest that this might result from induction of liver drug-metabolizing enzymes. Certainly, it has been shown that chlorpromazine causes enzyme induction in animals (Conney, 1967). However, in a recent report by Gram & Over0 (1972) there are indications that chlorpromazine inhibits the metabolism of imipramine in man. In our work, we have examined the effect of chlorpromazine on drug-metabolizing capacity in two situations-firstly, in schizophrenic patients receiving this drug and secondly, using isolated liver preparations from rats treated with chlorpromazine and, for comparison, with barbitone. Drug-metabolizing capacity in chlorpromazine-treated patients, in young control subjects and in elderly drug-free patients was assessed using the plasma antipyrine half-life technique, the dose, time of sampling and antipyrine estimations being as previously described (O’Malley, Crooks & others, 1971). Patients included in the study had been receiving chlorpromazine (150-600 mg) for at least 2 months and had not been given other drugs in that time. The phenothiazine was stopped approximately 10 h before ingestion of the test drug. Details of the animal study are as outlined in Table 2. From Table 1 it can be seen that the mean plasma antipyrine half-life in the chlorpromazine-treated patients was longer than in the younger controls (P < 0.001 ; students t-test) and was the same as that found in the elderly control subjects. Had enzyme induction occurred in the drug-exposed group a lower plasma antipyrine

The influence of digoxin-specific antibody fragments on digoxin disposition in the rat

Pentobarbitone-anaesthetized bile duct-cannulated female rats were injected intravenously with an equimolar dose of digoxin-specific sheep antibody fragments (DS-Fab) at 2 or 60 min after a dose of [3H]digoxin. The plasma drug levels were promptly elevated by 7-fold or 12-30-fold when the DS-Fab were given at 2 or 60 min respectively. When tissue drug concentrations were measured 2 min after a dose of DS-Fab (given 60 min after digoxin) which caused a 30-fold increase in plasma concentration, reductions could be detected if corrections were made for the presence in the tissues of high plasma concentrations of DS-Fab-bound drug. For instance, reductions in the heart, liver and small intestine were 63, 58 and 48% respectively. However, by 120 min after digoxin injection the only detectable effects on tissue drug concentration were in the kidney, where concentrations had increased 14-fold or 7-fold when the DS-Fab were given at 2 or 60 min respectively. Over the 120 min period the urinary excretion of digoxin-derived radioactivity was enhanced, and in the case where DS-Fab were given at 2 min, a 3-fold increase in urinary excretion was seen, which resulted in a net increase in the overall drug elimination. This greater urinary elimination was accompanied by a marked increase in the amount of bound drug in the urine (control and experimental values were 4 and 36% respectively). The cumulative biliary excretion of radioactivity seemed to be slightly reduced by DS-Fab administration at 2 or 60 min, although this was not statistically significant. A lack of significant drug-specific binding in the bile suggested that the liver is not involved in the elimination of hapten-DS-Fab complexes. There was little effect on the intestinal secretion of the drug.