Kate Franke

Absorption and disposition of chlordiazepoxide in young and elderly male volunteers.

T HE extensive prescribing of psychotropic drugs to elderly patients has generated considerable concern.1’2’8 Benzodiazepine derivatives are among the most widely administered class of psychotropic drugs,4’5 and several studies indicate that the incidence of unwanted side effects of various benzodiazepines (including chiordiazepoxide,#{176} diazepam,6 flurazepam,7 and nitrazepam8) is higher among elderly than among young individuals. The metabolic clearance of many drugs can become reduced in the elderly even when they are apparently healthy.9”#{176}’1’ However, age-dependent changes in benzodiazepine pharmacokinetics have been observed in some, but not all, studies in humans.8’213 To assess whether pharmacokinetic changes might be related to the increased sensitivity of elderly individuals to chlordiazepoxide,8 we compared the absorption and disposition of this drug in

Analysis of lorazepam and its glucoronide metabolite by electron-capture gas—liquid chromatography : Use in pharmacokinetic studies of lorazepam

Abstract This paper describes a rapid and sensitive method for analysis of lorazepam and its glucuronide metabolite in plasma and urine following therapeutic doses of lorazepam in humans. After addition of the structurally related benzodiazepine derivative, oxazepam, as the internal standard, 1-ml samples of plasma or urine are extracted twice at neutral pH with benzene (containing 1.5% isoamyl alcohol). The combined extracts are evaporated to dryness, reconstituted, and subjected to gas chromatographic analysis using a 3% OV-17 column and an electron-capture detector. Lorazepam glucuronide in urine is similarly analyzed following enzymatic cleavage with Glusulase. The sensitivity limits are 1–3 ng of lorazepam per ml of original sample, and the variability of identical samples is 5% or less. The applicability of the method to pharmacokinetic studies of lorazepam is demonstrated.

Impairment of antipyrine clearance in humans by propranolol.

SUMMARYThe effect of propranolol on antipyrine clearance in humans was evaluated in six healthy volunteers who received single 1.4 to 1.5 g doses of intravenous antipyrine on two occasions. The first (control) antipyrine trial was without concurrent drug administration; the second trial was done during treatment with therapeutic doses of propranolol (40 mg every 4 to 6 hours). Antipyrine elimination half-life (t/2), volume of distribution (Vd), and total clearance were determined after each trial. In all subjects isoproterenol sensitivity decreased markedly during propranolol treatment, indicating a high degree of beta blockade produced by the drug. Mean antipyrine t½/2 during the propranolol treatment period was significantly prolonged, and total clearance significantly reduced, over the control values. Twenty-four-hour urinary excretion of 4- hydroxyantipyrine, the major metabolite of antipyrine, likewise was reduced from 23.6% of the dose on the control trial to 14.8% of the dose during propranolol coadministration (0.1 < P < 0.2). Vd however, was nearly identical during both trials (0.62 L/kg). Thus propranolol prolongs the half-life and reduces the clearance or biotransformation rate of antipyrine, a drug whose clearance is independent of hepatic blood flow. Propranolol may influence the activity of hepatic microsomal enzymes responsible for drug hydroxylation.

Kinetics of intravenous chlordiazepoxide: Sex differences in drug distribution

Fourteen healthy subjects (7 male and 7 female) received 50 mg of chlordiazepoxide (CDX) hydrochloride by I‐hr intravenous infusion. Multiple venous blood samples drawn during the 72 hr after the infusion were assayed for whole blood concentrations of CDX and of its major metabolite, desmethylchlordiazepoxide (DMCDX). Mean (±SE) pharmacokinetic parameters, determined by weighted nonlinear least‐squares regression analysis, were: distribution half‐life, 1.3 (±0.3) hr; elimination half‐life, 17.8 (±2 .2) hr; volume of central compartment (VI), 0.27 (±0.02) Llkg; total distribution space (V.J, 0.52 (±0.03) Llkg; total clearance, 26.4 (±3.2) mllmin. Viand Vd were significantly larger among females (0.30 and 0.58 Llkg) than among males (0.22 and 0.45 Llkg), suggesting more extensive drug distribution in females. Values of half‐life and of clearance did not, however, differ significantly between sexes. A second study in three subjects compared simultaneous whole blood and plasma CDX concentrations after intravenous bolus injection and showed them to be highly correlated. Red cell :plasma partition ratios were 0, O.OJ, and 0.24, indicating limited uptake of CD X by red cells. Volumes of distribution and clearances calculated from CDX concentrations in whole blood are larger than those based on plasma concentrations.

Single and Multiple Dose Pharmacokinetics of Oral Quinidine Sulfate and Gluconate

Abstract The pharmacokinetics of oral quinidine sulfate and quinidine gluconate were compared in seven healthy volunteers In a two part pharmacokinetic study. Part I was a single dose crossover trial assessing absorption and elimination of quinidine sulfate (400 mg, equivalent to 331 mg of quinidine base) and quinidine gluconate (495 mg, equivalent to 309 mg of quinidine base). Mean kinetic values for the sulfate and gluconate preparations, respectively, were: peak serum quinidine level 2.07 versus 1.24 μg/ml (P Part II evaluated steady state kinetics of both preparations in a cross-over trial in the same subjects. Maintenance dosing schedules were 200 mg of quinidine sulfate every 6 hours versus 495 mg of quinidine gluconate every 12 hours. Systemic availability of the gluconate at the steady state level was 10 percent less (based upon area under the serum concentration curve) or 7 percent less (based upon urinary excretion of quinidine) than that of the sulfate, but the differences were not significant. Interdose fluctuation in serum quinidine concentrations during the gluconate trial averaged 70 percent, which was not significantly different from the average of 67 percent during the sulfate trial. However, variation within and between subjects in minimal steady state levels with quinidine gluconate (15.6 and 16.0 percent, respectively) was greater than with quinidine sulfate (7.2 and 9.9 percent, respectively). Steady state concentrations during the multiple dose trial were not accurately predicted from single dose pharmacokinetics, either for quinidine sulfate (r = 0.45) or quinidine gluconate (r = −0.12), but deviation of observed from predicted concentrations tended to be greater with quinidine gluconate. The slow absorption of quinidine from the gluconate preparation allows maintenance therapy on a 12 hourly dosage schedule with acceptable interdose fluctuation in serum levels. Variability within and between subjects in absorption kinetics tends to be greater with quinidine gluconate than with the more rapidly absorbed sulfate salt.

Influence of magnesium and aluminum hydroxide mixture on chlordiazepoxide absorption.

Ten healthy male subjects ingested 25 mg of chlordiazepoxide hydrochloride (Librium) with 100 ml of water or with 100 ml of magnesium and aluminum hydroxide (Maalox) in a single‐dose crossover study. Multiple venous blood samples drawn during the first 24 hr after each dose were assayed for concentrations of chlordiazepoxide and its major metabolite, desmethylchlordiazepoxide. The antacid prolonged the mean chlordiazepoxide absorption half‐time from 11 to 24 min, and in 6 of 10 subjects delayed achievement of the peak blood concentration by from 0.5 to 3.0 hrs. The formation of desmethylchlordiazepoxide was also slowed. The areas under the 24 hr blood concentration curve for chlordiazepoxide and for its metabolite were not influenced by the antacid. The apparent elimination half‐life of chlordiazepoxide (8.4 and 8.2 hr) was not significantly affected. Administration of chlordiazepoxide with antacid reduces the rate of its absorption but does not alter the completeness of absorption or the apparent rate of elimination.

Effect of Propranolol on Pharmacokinetics and Acute Electrocardiographic Changes following Intravenous Quinidine in Humans

5 healthy volunteers received 4–5 mg/kg of quinidine base by 15-min intravenous infusion on two occasions separated by at least 1 week. Multiple venous blood samples and all urine was collected during the 48 h after each dose and were analyzed for concentrations of total and unbound quinidine (following separation by equilibrium dialysis) by a double-extraction spectrophotofluorometric technique. The first quinidine administration was a ‘control’; for the second quinidine administration, propranolol (40 mg orally every 4–6 h) was given, starting 12 h before the quinidine dosage and continuing for the the duration of the trial. A high degree of β-blockade, assessed by intravenous isoproterenol sensitivity, was achieved by propranolol treatment. Mean (± SE) kinetic variables for quinidine during control and propranolol trials, respectively, were: volume of distribution, 3.0 ± 0.5 versus 2.9 ± 0.5 1/kg (NS); elimination half-life, 7.8 ± 1.1 versus 7.6 ± 0.7 h (NS); total clearance, 4.5 ± 0.6 versus 4.3 ± 0.6 ml/min/kg (NS); renal clearance, 1.58 ± 0.2 versus 1.57 ± 0.2 ml/min/kg (NS); percent unbound, 23.0 ± 1.1 versus 23.6 ± 1.3% (NS). Intravenous quinidine produced tachycardia, T-wave flattening, and prolongation of the QT-interval; none of the changes were influenced by propranolol coadministration. Thus propranolol did not significantly alter the pharmacokinetics or acute electrocardiographic effects of intravenous quinidine in healthy volunteers.

Absorption of oral and intramuscular chlordiazepoxide.

SummaryThe absorption of oral and intramuscular (i. m.) chlordiazepoxide hydrochloride (CDX · HCl) was compared in two pharmacokinetic studies. In Study One, single 50-mg doses of CDX · HCl were administered orally and by i. m. injection to 14 healthy volunteers using a crossover design. Whole-blood concentrations of chlordiazepoxide (CDX) and its first active metabolite, desmethylchlordiazepoxide (DMCDX), were determined in multiple samples drawn after the dose. Mean pharmacokinetic variables for CDX following oral and i. m. administration, respectively, were: highest measured blood concentration, 1.65 vs 0.87 µg/ml (p<0.001); time of highest concentration, 2.3 vs 7.6 h after dosing (p<0.001); apparent absorption half-life, 0.71 vs 3.39 h (p<0.001). Biphasic absorption after i. m. injection, consistent with precipitation at the injection site, was observed in 9 of 14 subjects. Based upon comparison with previous intravenous data, the completeness of absorption was 100% for oral vs 86% for i. m. CDX · HCl (p<0.1). In Study Two, 28 male chronic alcoholics with clinical manifestations of the acute alcohol withdrawal syndrome were randomly assigned to one of four treatment conditions: 50 or 100 mg doses of CDX · HCl, by mouth or by i. m. injection. Concentrations of CDX and DMCDX, determined in plasma samples drawn every 20 min for 5 h following the dose, were significantly higher after oral administration of a given dose than at corresponding points in time after i.m. injection after the same dose. Thus absorption of oral CDX is reasonably rapid and complete, whereas the absorption rate of i. m. CDX is slow.

Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients.

Thirty otherwise healthy patients received a 100‐mg oral dose of chlordiazepoxide HCl just prior to surgical procedures using spinal anesthesia. Fourteen of these patients had also received 100 mg on the night before surgery. Simultaneous sampies of venous blood and cerebrospinal fluid (CSF) were taken immediately prior to injection of spinal anesthesia and were assayed for concentrations of chlordiazepoxide (CDX) and its major metabolite, desmethylchlordiazepoxide. Plasma concentrations of CDX ranged from 2.32 to 13.34 µg/ml. Simultaneous CSF concentrations were considerably lower, ranging from 0.04 to 0.34 µg/ml. Equilibration of CDX between plasma and the lumbar sampling site appeared to be complete within 2 hr of the most recent dose. After attainment of distribution equilibrium, simultaneous plasma and CSF concentrations of CDX were highly correlated (r = 0.76), with a mean CSF‐plasma concentration ratio of only 0.043 (range; 0.02 to 0.06). The limited passage of CDX into human CSF is probably due to extensive binding (0 plasma protein. Assuming that transfer of CDX from plasma to CSF is governed by passive diffusion, the extent of plasma protein binding of CDX in healthy individuals averages about 96%.

Factors influencing blood concentrations of chlordiazepoxide: a use of multiple regression analysis.

Three groups of male and female subjects aged 24–74 years received 25, 100, or 200 mg of chlordiazepoxide hydrochloride by mouth as a single dose or as two divided doses. The relation of plasma or whole blood concentrations for chlordiazepoxide (CDX) and its metabolite, desmethylchlordiazepoxide (DMCDX), to time since the last dose, weight, age, and sex were determined by simple and multiple regression analyses. Both CDX and DMCDX levels were negatively correlated with weight. Concentrations of CDX decreased, while those of DMCDX increased, with the time since the last dose. Lower levels of both drugs were associated with female sex, and lower levels of DMCDX were noted with increasing age. In the largest sample group, age and weight were more important variables than sex in accounting for CDX and DMCDX. Sex was of significance, and more important than time or age in explaining the variance of CDX in one series of observations. Multiple regression analysis is a useful approach to assessing interrelated factors influencing blood levels of drugs, especially when combined with a consideration of the interactive components of variance. Age and sex, in addition to weight and time, may be important factors that deserve further attention.