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Biomedical subjects

G R Wilkinson

Publications and source records attributed to G R Wilkinson.

At least 145 records · Page 8Linked to original sources
PubMed1980

Propranolol disposition in renal failure.

1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]-propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/- 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/- 0.059 to 3.326 +/- 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half-life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady-state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.

Administration, Oral↗
PubMed1980

Effect of heparin administration on plasma binding of benzodiazepines.

1 The effect of intravenous administration of 100 units of heparin on plasma of diazepam, chlordiazepoxide, oxazepam and lorazepam was examined in fourteen normal subjects and five patients with cirrhosis. 2 In normal non-fasted subjects heparin caused a rapid 150--250% rise in the free fraction of diazepam, chlordiazepoxide and oxazepam but no change of lorazepam. The changes in free fraction were slightly smaller, but still significant, when the subjects were fasted. 3 These change in free fraction occurred within 90 s of administration of heparin and binding had returned to baseline by 30 to 45 min. 4 In the cirrhotic subjects the response to heparin was variable. 5 The use of heparin during drug disposition studies may affect the estimation of pharmacokinetic parameters and possibly pharmacological effects which are dependent on the circulating unbound drug level.

Anti-Anxiety Agents↗
PubMed1980

Elevated plasma free drug concentrations of propranolol and diazepam during cardiac catheterization.

Patients who undergo cardiac catheterization are frequently taking propranolol and are often premedicated with diazepam. Because the intensity of a drug's action is determined by free, or non-protein-bound, levels in plasma, changes in the degree of protein binding may profoundly alter the pharmacologic effect. We examined the effects of heparin on the free levels of propranolol and diazepam in six patients who underwent cardiac catheterization. After heparinization, the free fraction of diazepam increased more than fourfold, from 1.8 +/- 0.1% to 7.9 +/- 1.2% (p < 0.002) and the free levels increased from 2.0 +/- 0.5 to 8.4 +/- 2.2 ng/ml (p < 0.025); the free fraction of propranolol increased from 7.4 +/- 0.9% to 12.5 +/- 1.4% (p < 0.001). The increase in free drug concentration was associated with elevated free fatty acid levels, which rose from 181 +/- 7 micrograms/ml to 596 +/- 119 micrograms/ml (p < 0.02). Increases in the free levels of propranolol and diazepam produced by heparinization during cardiac catheterization may result in increased pharmacolaogic effect, such as excessive sedation or respiratory depression.

Adult↗
PubMed1979

Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives.

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.

Adolescent↗
PubMed1979

Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination.

The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.

Adult↗
PubMed1979

Plasma binding of benzodiazepines in humans.

Plasma binding of chlordiazepoxide, diazepam, loraxepam, and oxazepam was determined by equilibrium dialysis in 20 male, healthy volunteers, 25-86 years old. A wide range of binding was observed, with the free fraction varying twofold for lorazepam, fourfold for chlordiazepoxide and diazepam, and over 20-fold for oxazepam. Statistically significant linear relationships were not observed between the degree of binding and age, serum albumin, or total protein for any of the drugs. There was, however, a correlation between the extent of binding for the four drugs. Because of the importance of unbound benzodiazepine levels in eliciting any pharmacological response and also in disposition, consideration of the wide interindividual variability in plasma binding must be made in interpreting pharmacodynamic and pharmacokinetic data.

Adult↗
PubMed1978

Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man.

The dose and plasma levels of indomethacin correlated with inhibition of prostaglandin synthesis as measured both by urinary excretion of the major metabolite of prostaglandin E2 (PGE-M) and by the release of prostaglandin E2 from thrombin-stimulated platelets. Considerable intersubject variability was observed in the suppression of PGE-M excretion. In some patients 37.5 mg indomethacin daily, usually considered subtherapeutic, caused suppression. Maximal suppression (greater than 90%) occurred in some after a daily dose of 75 mg, whereas 150 mg was required to achieve this level of inhibition in others. Suppression of the excretion of PGE-M by 60% occurred when the end of the dosage interval plasma levels of indomethacin were in the range 0.05 to 0.3 microgram/ml, which implies that a somewhat higher average steady-state concentration during the dosage interval was required to achieve this effect. A similar degree of inhibition of the release of PGE2 on thrombin-stimulated platelets was associated with the same range of plasma levels. Upon discontinuation of the drug, the levels of indomethacin in plasma decreased exponentially; inhibition of the release of PGE2 from platelets by indomethacin declined linearly with time and in parallel with the logarithm of the diminishing plasma levels.

Adult↗
PubMed1978

Direct measurement of propranolol bioavailability during accumulation to steady-state.

1. A high performance liquid chromatographic method for the determination of propranolol in human plasma and blood has been developed and used to confirm that cumulation occurred during chronic oral administration, steady-state being achieved within 48 h of beginning 80 mg of the drug every 8 h. 2. The method was adapted to measure [H3]-propranolol and native drug in the same blood sample and was applied to determine simultaneously the disposition of i.v. ([H3]-propranolol) and orally (non-labelled) administered drug after single oral dose of 80 mg and when steady-state had been established on an 80 mg, 8-hourly regimen. 3. Using this approach it was possible to show that a reduced oral clearance at steady-state was associated with a smaller reduction in systemic (i.v.) clearance and no change in liver blood flow. A direct estimate of bioavailability was also possible and was found to be increased at steady-state compared with a single oral dose. 4. We conclude that the accumulation of propranolol during the attainment of steady-state is due to a reduction in intrinsic clearance, resulting in reduced presystemic hepatic extraction.

Administration, Oral↗
PubMed1978

Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide (librium).

There is an increased incidence of unwanted sedation associated with chlordiazepoxide usage in the elderly and in patients with liver disease. To determine whether pharmacokinetic alterations could account in part for these observations we studied the disposition and elimination of intravenously administered chlordiazepoxide in 27 healthy controls aged 16 to 86 years, 8 patients with cirrhosis, and 5 patients with acute viral hepatitis. Both increasing age and parenchymal liver disease led to similar changes in chlordiazepoxide pharmacokinetics. Over the age range 20 to 80 years, elimination half-life (t1/2(beta)) increased from 7 to 40 hr (r, 0.67; P less than 0.001) attributable to a decrease in plasma clearance from 30 ml per min to 10 ml per min (r, -0.71; P less than 0.001) and an increase in volume of distribution from 0.26 to 0.38 liters per kg (r, 0.60; P less than 0.05). Similarly, a decrease in plasma clearance in cirrhosis (7.7 +/- 2.1 compared to 15.3 +/- 4.4 ml per min, P less than 0.01) and acute viral hepatitis (6.1 +/- 4.3 compared to 18.1 +/- 7.1 ml per min, P less than 0.01) relative to age-matched controls and an increase in the volume of distribution resulted in a prolongation of the elimination half-life in both forms of liver disease. Impaired elimination of chlordiazepoxide may account in part for the increased incidence of oversedation seen in the elderly and in patients with liver disease.

Adolescent↗
PubMed1978

The influence of indomethacin on the pharmacokinetics, diuretic response and hemodynamics of furosemide in the dog.

Indomethacin has the potential to interact with furosemide in a number of different fashions. We have investigated some of these possibilities in seven mongrel dogs that received furosemide (2 mg/kg i.v.). Plasma and urinary concentration of furosemide were measured by high performance liquid chromatography, diuretic response was assessed by urinary sodium excretion and renal blood flow and its distribution were estimated using the radioactive microsphere technique. Furosemide induced a prompt diuresis associated with a 50% increase in total renal blood flow. Intrarenal blood flow was preferentially increased in the inner cortical zones. Furosemide was rapidly eliminated with a renal clearance that was 35% of the total systemic clearance. Maximal sodium excretion was attained at plasma furosemide concentrations greater than 0.8 microgram/ml; below this concentration there was a linear relationship between plasma concentration and rate of sodium excretion. The ratio of sodium/furosemide concentration in urine rose to a plateau, then remained constant. Indomethacin pretreatment inhibited the hemodynamic response to furosemide. In addition, indomethacin reduced the renal and extrarenal clearance of furosemide by approximately 30%, but did not change the proportion of unchanged drug excreted in the urine. Although the diuretic response for any given plasma concentration of furosemide was reduced, the ratio of urinary sodium/furosemide concentration was not changed by indomethacin. Since the amount of furosemide reaching the urine was not altered, the total diuretic response was not significantly affected by indomethacin. From these observations we conclude that indomethacin alters the pharmacokinetics of the disposition of furosemide and furosemide-induced renal hemodynamic changes. However, our data indicate that the response of the renal tubule to furosemide secreted into tubular fluid is not changed by indomethacin.

Animals↗