Verapamil kinetics have been determined in liver disease (mainly in cirrhotic patients), in intensive-care patients, and in healthy control subjects. Areas under the concentration-time curves (AUCs) after intravenous 5-mg and oral 80-mg doses were used to calculate systemic blood clearance, intrinsic blood clearance, and bioavailability of verapamil in patients and to calculate apparent hepatic blood flow. Intravenous data showed that verapamil clearance was reduced in all patients with liver disease (mean = -66%), but intensive-care patients were a more heterogenous group in which some patients had increases (five patients; mean = +72%) and others had decreases (two patients; mean = 6-57%) in verapamil clearance. The changes in clearance corresponded to changes in the half-time for the beta-phase (t1/2 beta). Verapamil bioavailability is low, and the intensive-care patients and healthy subjects examined it ranged from 13% to 21%. There was considerable variation in liver disease subjects, in whom verapamil bioavailability ranged from 3.8% to 64%. THe systemic clearance of verapamil correlated linearly with calculated apparent hepatic blood flow (r = 0.99; regression coefficient = 0.87). In the case of one liver patient the kinetic results could be used to confirm the clinical diagnosis of hepatic shunts. It is concluded that there are clinically significant changes in verapamil elimination in liver disease and in intensive-care patients. For patients with normal hepatic vascular anatomy, these changes can be explained in terms of differences in hepatic blood flow.

The pharmacokinetics of hexobarbitone were investigated in 22 patients in an intensive care unit. The results were compared with those obtained in a healthy group for three time periods: 3rd or 4th day (I), 5-8th days (II) and 13-29th days (III) of treatment. Hexobarbitone 7.32 mg per kg of body weight was administered by i.v. infusion in 60 min. At the end of the infusion, the mean plasma concentration of group I was 71% greater than control group; groups II and III were near to control. In all patients the post-infusion concentration-time course of hexobarbitone could be described by two-compartment kinetics. The biphasic decrease in plasma concentration of hexobarbitone was more rapid in groups II and III, than in either the control group or in group I. At the beginning of treatment patients generally showed an unchanged hexobarbitone half-life, a slightly decreased plasma clearance, a reduction of approximately 50% of the initial distribution volume. (V1) and a reduction of 44% of the distribution volume at steady state. In groups II and III the mean of these values were comparable to control. However, plasma clearance had increased by about 87% in group II compared with control, and after 2-3 weeks (group III) by about 143%. Correspondingly, half-life was reduced by 45% and 58% respectively. The pharmacokinetics were not related to change in liver function. The presence of clinical and bacteriological signs of septicaemia was closely associated with an enhanced hexobarbitone clearance.

Binding kinetics at the benzodiazepine binding site of albumin have been determined as a function of age and fatty acid concentration in serum from 32 neonates (umbilical cord blood), 28 adults aged 23‐65 years and 24 adults aged 66‐101 years using fluorescence‐time curves obtained in a Durrum‐Gibson stopped‐flow apparatus and the specific marker ligand dansylsarcosine. The binding reaction can be described by a 2‐step mechanism characterised by four constants: the association rate constant k2 and dissociation rate constant k‐2 for the rate limiting step‐2; the affinity constant KA' for the formation of an unstable intermediate complex in step‐1; the affinity constant KA for the overall reaction. There were marked differences in k2 between the three groups of subjects with highest values occurring in neonates (mean: 296 s‐1), intermediate values in adults aged 23‐65 years (mean: 200 s‐1, P less than 0.001) and lowest values in adults aged 66‐101 years (mean: 144 s‐1, P less than 0.001). The dissociation rate constants (k‐2) averaged 18.5 s‐1 overall, showed only minor changes with increasing age and corresponded to dissociation half‐lives of 42 ms, 38 ms and 33 ms for neonates, adults 23‐65 years and adults 66‐101 years respectively. KA' in neonates and in the group of elderly subjects were lower than in adults aged 23‐65 years.(ABSTRACT TRUNCATED AT 250 WORDS)