1 The plasma protein binding of theophylline was determined after addition of ['4C]-theophylline (15 ,g/ml) to plasma from 24 healthy drug-free volunteers and equilibrium dialysis for 2 h at 37°C. 2 The percentage of drug unbound was 60.0% 2.2% (s.d.) with very little variation between individuals. The binding ratio of theophylline was not significantly related to the plasma albumin or a,-acid glycoprotein (AAG) concentrations but was significantly, although weakly, negatively related to the logarithm of the non-esterified fatty acid concentration (NEFA) (r = 0.443, P < 0.05). 3 Intravenous administration of heparin (1000 units) caused a significant rise in plasma NEFA concentration and in the percentage of drug unbound in plasma after equilibrium dialysis. 4 In human serum albumin solutions, the binding ratio of theophylline was significantly related to the albumin concentration and at the albumin concentration seen in the 24 normal subjects, the percentage of drug unbound was almost identical. Addition of AAG in physiological concentrations did not enhance theophylline binding but oleic acid, and to a lesser extent palmitic acid, reduced binding significantly. 5 The percentage of theophylline unbound in plasma varied markedly with pH so that at pH7 the percentage unbound was 52% greater than at pH 8. There was no evidence of concentration dependence of binding up to 140 ,ug/ml theophylline.6 Theophylline appears to bind almost exclusively to albumin and its plasma protein binding varies little in healthy subjects, showing no concentration-dependence over the therapeutic range of concentrations. The binding is affected by pH and by NEFA concentration, however, and these factors may be of greater importance in disease states. Caution should be employed in the use of heparin in studies of plasma protein binding of theophylline.

The plasma protein binding of phenytoin was investigated in 56 epileptic patients attending the outpatient clinc. The free phenytoin fraction was measured by equilibrium dialysis at 37°C and the total concentration by a homogenous enzyme immunoassay technique. The free fraction ranged from 0.123 to 0.177 (median 0.144, mean + s.d. = 0.145 + 0.012). Distribution was consistent with normality. Four of the patients were also taking sodium valproate. The median free fraction of phenytoin in these patients was 0.174, 21% higher than that of the total group (P < 0.05).The total concentration of phenytoin varied from 0.3 to 29.4 4g/ml (median 12 ,ug/ml, mean + s.d. = 13.31 + 6.13 ,g/ml) and the free fraction was not related to the total drug concentration. There was a highly significant relationship between free phenytoin concentration and total phenytoin concentration (r = 0.986, P < 0.001). There appears to be very little variability in protein binding of phenytoin in epileptic patients and thus total plasma phenytoin concentration closely reflects the free (unbound) drug concentration. Routine estimation of free plasma phenytoin concentration is therefore unnecessary and should be reserved for those patients where alteration in binding is likely, e.g. renal or hepatic disease or where adverse effects occur at unexpectedly low total phenytoin concentrations.

The plasma protein binding of metoclopramide was measured after addition of the drug (60 ng ml‐1) to plasma from 18 patients with renal disease and 18 age and sex matched healthy individuals. The mean free fraction in renal disease (0.59 range 0.41‐0.71) was not significantly different from controls (mean 0.6 range 0.56‐0.69). In both groups the binding ratio of metoclopramide was significantly related to plasma alpha 1‐acid glycoprotein (AAG) concentration but not to albumin or plasma non‐esterified fatty acids concentration. Metoclopramide bound to human serum albumin (HSA) to a limited extent and to human AAG to a greater extent indicating that AAG is the major binding protein for the drug in plasma.

SUMMARYBackground: Transdermal nicotine is of value in active ulcerative colitis but causes adverse events because of systemic absorption. Nicotine enemas may give rise to fewer adverse events. Aim: To assess the pharmacokinetics of nicotine enemas in three doses. Methods: Thirteen volunteers, all non-smokers but three ex-smokers, were given enemas on separate occasions containing 3, 6 and 9 mg of nicotine, in ascending dose order. Adverse events were recorded and blood samples taken over 8 h for measurement of serum nicotine and cotinine. Results: Enemas were retained by most subjects. Eleven of 14 adverse events were 'early' -30-105 min after

Aims We investigated the effects of repeated‐dose charcoal administered several hours after sodium valproate on the pharmacokinetics of a single dose of the drug in healthy volunteers. Methods The pharmacokinetics of sodium valproate were studied in seven healthy volunteers after administration of a syrup (300 mg) on two occasions, one of which was followed by administration of repeated doses of oral charcoal starting 4 h after the drug up to 32 h (total dose 80 g). Results Valproate was rapidly absorbed with maximum concentrations 1 h after administration. The area under the plasma concentration‐time curve to 48 h (AUC (0,48 h)) was 408 ± 114.5 (s.d.)mgl−1 h in the control phase and 398 ± 108.6 mgl−1 h after charcoal and the t1/2 elimination was 20 ± 6.8 h in the control phase, and 22 ± 9.2 h after charcoal (NS). Conclusions Repeated‐dose activated charcoal does not appear to enhance the rate of elimination of sodium valproate after therapeutic doses of the drug and any beneficial effect of charcoal in overdose may be to prevent absorption of valproate still present in the gut.

Amiodarone is an effective antiarrhythmic agent whose use is associated with several drug interactions one of which is potentiation of the action of warfarin. The mechanism of this interaction has hitherto been unclear. We examined possible mechanisms in eight patients. Total plasma warfarin clearance was found to be reduced by amiodarone. No change was detected in the binding of warfarin to plasma proteins. No relationship was found between plasma amiodarone concentrations and the change in warfarin clearance.

Total plasma and mixed stimulated saliva theophylline concentrations (by high performance liquid chromatography) and free plasma theophylline concentrations (by equilibrium dialysis) were measured in simultaneously collected samples from 32 outpatients receiving chronic oral theophylline treatment, who had received the drug at least two hours before sampling. There was a close relationship between saliva and total plasma theophylline concentration and between total saliva and free plasma concentration. The mean saliva to total plasma drug concentration ratio was 0.69 (SE 0.09) and the mean difference between paired saliva and free plasma concentration was 0.65 (0.17) ,g/ml. It is concluded that stimulated mixed saliva provides a simple, non-invasive method of assessing total (and free) plasma theophylline concentrations during chronic oral treatment. The therapeutic range for saliva, corresponding to the generally accepted total plasma concentration range (10-20 ,ug/ml), is approximately 7-14 ,ug/ml.The measurement of plasma theophylline concentrations has been shown to be cf value in management of patients with chronic reversible airflow obstruction.' Such measurements require blood sampling, which is invasive and uncomfortable and requires trained personnel. The saliva concentration of some drugs (for example, phenytoin) has been shown to be closely related to the plasma concentration of the free drug and saliva has proved to be a useful alternative method of assessing drug concentration, particularly patients for whom blood sampling is difficult or inconvenient.2Relatively few studies have examined the relationship between saliva and plasma total theophylline concentrations and they have produced varying results in adults receiving chronic oral therapy.6 Only one study examined the relationship between saliva and free (unbound) plasma theophylline concentration,6 the moiety which in part determines the saliva concentration2 and where

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