Hans J. Dengler

Diazepam Kinetics in Relation to Age and Sex

27 male volunteers aged 20 to 91 years, and 13 female volunteers aged 21 to 33 years, received single 5 to 10 mg doses of diazepam intravenously. Diazepam pharmacokinetics were determined from concentrations measured in multiple plasma samples drawn during 7 days after each dose. Diazepam elimination half-life among males (mean: 66 h) increased significantly with age (r = 0.53, p less than 0.005). Volume of distribution (mean: 1.39 liters/kg) also increased significantly with age (r = 0.67, p less than 0.001). Clearance of total diazepam in males (mean: 0.42 ml/min/kg) tended to decline with age (r = 0.32), but the association was of borderline significance (p = 0.1). Diazepam was extensively bound to plasma protein, with a mean free fraction among male subjects of 1.34%. Free fraction tended to increase with age (r = 0.14). Correction of volume of distribution and clearance for individual differences in binding did not alter the conclusions. Compared to young males, young females had larger volumes of distribution (1.87 vs. 1.34 liters/kg) and higher total clearance (0.63 vs. 0.49 ml/min/kg). These differences were even greater after correction for sex-related changes in protein binding. Elimination half-life did not differ between sexes. Since both age and sex can influence diazepam disposition, both should be considered as independent variables in studies of diazepam pharmacokinetics.

Diazepam interaction with antituberculosis drugs

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug‐free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half‐life (t½) from 34 to 45 hr (p < 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p < 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healthy drug‐free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t½ among patients (14 hr) was significantly shorter than in controls (58 hr, p < 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p < 0.01). Study 3 compared six newly diagnosed tuberculous patients receiving initial therapy with EMB alone with age‐ and sex‐matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and txh prolonged by administration of INH alone. Markedly increased clearance and shortened t½ in triple‐therapy patients is probably due to enzyme‐inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

Influence of thyroid status on plasma half-life of antipyrine in man.

Abstract The half-life of antipyrine in plasma was studied In four hyperthyroid and four hypothyroid patients before and after thyroid status returned to normal. The half-life (± S.E.M.) was 7.9 ± 1.0 hours In hyperthyroid and 17.3 ± 1.1 hours in hypothyroid patients. After correction of the abnormal thyroid state the half-life values of both groups (12.3 ± 0.7 and 12.0 ± 0.5 hours) were within the normal range. These results suggest that abnormalities of thyroid function can markedly influence human metabolism of some drugs. (N Engl J Med 290:1040–1042, 1974)

The effect of pindolol on exercise-induced cardiac acceleration in relation to plasma levels in man.

The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10‐mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.

Diazepam absorption: effects of age, sex, and Billroth gastrectomy.

The kinetics of diazepam absorption were assessed in 37 healthy volunteers, aged 19–79 years, who ingested a single 5-mg tablet in the fasting state. Diazepam plasma concentrations were measured by gas chromatography in multiple samples drawn over the next 72 hr. After a lag time averaging 12 min elapsed between tablet ingestion and the start of absorption, first-order absorption proceeded with a mean half-life of 19 min (range: 0–96 min), with peak plasma concentrations reached 0.9 hr after dosage (range: 0.25–2.5 hr). Age and sex did not influence absorption kinetics. Peak plasma concentrations averagd 157 ng/ml, and tended to be higher in women than in men because of lower body weights in women. Peak levels also declined with age, probably due to increased volume of distribution of diazepam in the elderly. Absolute systemic availability of oral diazepam was evaluated in seven of the subjects who received intravenous diazepam on another occasion. Based on areas under the oral versus intravenous plasma concentration curve, bioavailability of diazepam averaged 97%. Six male patients, at least 2 years after undergoing Billroth gastrectomy, also participated in the diazepam absorption study. Absorption kinetic parameters were nearly identical to those in six healthy agematched male volunteers without gastrointestinal disease. Thus absorption of oral diazepam in the fasting state is rapid and nearly complete, and is minimally influenced by age, sex, or Billroth gastrectomy.

Noninteraction of Digitoxin and Quinidine

A LARGE and clinically important interaction between digoxin and quinidine is now well documented.1 2 3 4 5 The cardiac glycoside digitoxin is extensively used in clinical practice, but its interaction with quinidine has not been definitively evaluated.6 , 7 In this study, which assessed the pharmacokinetic interaction of digitoxin with quinidine, we found that simultaneous administration of quinidine had no statistically significant effect on the distribution or clearance of intravenously administered digitoxin. Methods Ten healthy male and female volunteers participated after giving informed consent (Table 1). Their ages ranged from 23 to 32 years. None had evidence of medical disease, and none were taking medications .xa0.xa0.

Absorption of oral tetracycline in patients with Billroth-II gastrectomy.

The bioavailability of a single 250-mg oral dose of tetracycline hydroghloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significant differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 μg/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4hr), or the apparent first-order elimination half-life (8.0 vs. 8.7hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth -II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.

Disease-related alterations in cardiac glycoside disposition.

SummaryThe effects of diseases involving the kidney, gastrointestinal tract, thyroid, and cardiovascular system on the disposition of cardiac glycosides are reviewed.The glycosides ouabain and digoxin are cleared predominantly by renal excretion of the intact drugs. Not surprisingly, total clearance of these two compounds is reduced in patients with reduced Creatinine clearance. Similarly, steady-state serum concentrations of digoxin at any given dose become higher as renal function declines. However, individual variability is considerable, thereby limiting the utility of dosage schemes based on nomograms or equations. A further complication is that tissue distribution of digoxin is altered in renal insufficiency, so that serum concentrations take on u different meaning in patients with renal failure. In the case of digitoxin, renal clearance accounts for only part of the total clearance. A clear relationship between Creatinine clearance and total digitoxin clearance has not yet been established. However, digitoxin protein binding is reduced in renal insufficiency, requiring a change in the clinical interpretation of total (free plus bound) digitoxin serum concentrations in such patients.Although digoxin absorption may be impaired in patients with serious malabsorption syndromes, most studies have demonstrated normal or near normal absorption despite gastrointestinal disease or extensive ablative surgery. Hepatic cirrhosis does not alter the pharmacokinetics of digoxin, but is associated with impaired demethylation of β-methyldigoxin (medigoxin). Although hepatic biotransformation accounts for a substantial fraction of the total clearance of digitoxin, disappearance of digitoxin from the plasma is, if anything, more rapid in patients with liver disease as opposed to healthy controls.Clearance of both digitoxin and digoxin varies in direct relation to thyroid function; clearance is increased and the half-life shortened in thyrotoxicosis, and the reverse is true for hypothyroidism. This may be explained by parallel changes in Creatinine clearance, but further studies are needed to define the mechanism of alterations in glycoside clearance in relation to thyroid function.Continuing refinement of analytical and pharmacokinetic techniques will lead to rapid progress in research in this area, and a need for continuing re-evaluation of the state of the art.

Further analysis of sparteine oxidation in a Japanese population and comparison with data observed in different ethnic populations

1. Data on the oxidation polymorphism of sparteine (SP) studied in 84 unrelated Japanese subjects of whom two (2.4%) were classified as poor metabolizers (PMs) were re-evaluated. The data were obtained from 6-hour urinary excretion ratios of SP to 2- and 5-dehydrosparteines (DHS), after an oral dose of 100 mg of SP sulphate. 2. Urinary excretion of both SP and DHS correlated with the SP/DHS ratio (rs = 0.862 and -0.756, respectively, P less than 0.001). In addition, urinary excretion of 2-DHS, 5-DHS or total DHS discriminated between PMs and extensive metabolizers (EMs). There was also a highly significant correlation (rs = 0.669, P less than 0.001) between the urinary excretion of 2- and 5-DHS. 3. These re-evaluated results on the oxidation polymorphism of SP indicate that 2- and 5-DHS formation from SP shares a common metabolic pathway (presumably via the same P-450 isozyme), and that the SP/DHS ratio, conventionally used as a discriminating index between PMs and EMs, quantitatively reflects the capacity of 2- and 5-DHS formation. 4. The benefit of using a shorter (6 h) collection period for assessing the individual oxidation phenotype of SP and inter-ethnic comparison of SP oxidation is also discussed.

Endogenous ligand(s) decrease drug--protein binding in uremic sera: a fluorescence probe study.

SummaryHuman serum albumin (HSA) was isolated and purified (>97% purity) from normal sera, from sera of patients with severe chronic renal insufficiency and from sera to which a strongly protein bound acidic drug — clofibrinic acid — was added as a model ligand. The binding properties were evaluated using dansylglycine as a fluorescent probe. Data were analyzed according to Scatchard, the binding constants were calculated by least square approximation. The binding of dansylglycine to HSA from uremic sera was substantially decreased, reflected mainly by a lower productn1·K1, as was the binding of dansylglycine to HSA from model sera containing clofibrinic acid. The binding was restored to almost normal when HSA was treated with charcoal. It is concluded that the impaired binding of many mostly acidic drugs to HSA in uremia is due to the presence of endogenous ligands. In addition a minor contribution by changes in HSA structure cannot be excluded.