Hermann R. Ochs

Reduction in Lidocaine Clearance during Continuous Infusion and by Coadministration of Propranolol

LIDOCAINE is commonly administered parenterally for the treatment of cardiac arrhythmias. The use of this drug is complicated by its narrow therapeutic index.1 Any reduction in its metabolic cleara...

Clinical Pharmacokinetics of the Newer Benzodiazepines

SummaryNew benzodiazepine derivatives continue to be developed and introduced into clinical use. The pharmacokinetic properties of these newer drugs can best be understood by their categorisation according to range of elimination half-life and pathway of metabolism (oxidation versus conjugation). Clobazam and halazepam are long half-life (and therefore accumulating) anxiolytics metabolised by oxidation. Alprazolam and clotiazepam also are oxidised compounds but have short to intermediate half-life values and therefore produce considerably less accumulation. Temazepam and lormetazepam are hypnotic agents with intermediate half-lives but metabolised by conjugation. The most unique of the newer benzodiazepines are the ultra-short half-life (oxidised) compounds midazolam, triazolam and brotizolam, which are essentially non-accumulating during multiple dosage.

Clinical Pharmacokinetics of Quinidine

SummaryThe elimination of quinidine in humans is accomplished by a combination of renal excretion of the intact drug (15 to 40% of total clearance) and hepatic biotransformation to a variety of metabolites (60 to 85% of total clearance). Many of the metabolites appear to be pharmacologically active. Typical ranges for kinetic properties of quinidine in healthy persons are: apparent volume of distribution 2.0 to 3.5 litres/kg: elimination half-life 5 to 12 hours; clearance, 2.5 to 5.0ml/min/kg. Quinidine clearance is reduced in the elderly, in patients with cirrhosis, and in those with congestive heart failure.Oral quinidine is available either as relatively rapidly absorbed conventional tablets (usually quinidine sulphate) or as a variety of slowly absorbed sustained release preparations. Absolute systemic availability generally is 70% or greater.Quinidine is 70 to 95% bound to plasma protein, primarily to albumin but also to a number of other plasma constituents. Binding is reduced in patients with cirrhosis, partly because of hypoalbuminaemia, but is not influenced by renal insufficiency. Clinical interpretation of total serum or plasma quinidine concentrations must be altered in patients with reduced or increased binding, since it is the unbound fraction which is pharmacologically active.

Entry of diazepam and its major metabolite into cerebrospinal fluid

Five dogs received a single 1.0 mg/kg dose of diazepam (DZ) IV. Concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were simultaneously measured in plasma and cisternal cerebrospinal fluid (CSF) for up to 8 h after the dose by electron-capture gas-liquid chromatography. DZ was rapidly eliminated from plasma (half-life 0.3–1.3 h); DZ disappearance was mirrored by formation of DMDZ, which in turn was eliminated slowly. Both DZ and DMDZ rapidly penetrated CSF and concentrations in CSF declined parallel with those in plasma. Despite rapid uptake, the extent of CSF transfer of DZ and DMDZ was limited by plasma protein binding. Mean CSF: plasma concentration ratios for DZ (range 0.023–0.137) and DMDZ (range 0.047–0.119) were highly correlated with the unbound fraction in plasma (r=0.95 and 0.80, respectively). Thus DZ and DMDZ concentrations in CSF, presumed to reflect concentrations at the site of action, are determined by unbound plasma concentrations. The intensity of pharmacologic action is more likely to correlate with unbound than with total plasma concentrations.

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.

Trazodone kinetics: Effect of age, gender, and obesity

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P < 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P < 0.05), thereby increasing elimination half‐life (t½) in elderly men (8.2 vs. 4.7 hours; P < 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P < 0.02), causing increased t½ (7.6 vs. 5.9 hours; P < 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P < 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t½ in obese subjects (13.3 vs. 5.9 hours; P < 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

Automated Gas Chromatography for Studies of Midazolam Pharmacokinetics

Plasma midazolam concentrations following single therapeutic doses can be quantitated using electron-capture gas-liquid chromatography. After addition of a benzodiazepine analogue as an internal standard, samples are extracted with benzeneisoamyl alcohol (98.5:1.5). The organic extract is evaporated to dryness, reconstituted, and chromatographed on an SP-2250 liquid phase. The automatic sampler allows up to 100 chromatographic analyses per 24-h period. The sensitivity limits are 2-3 ng of midazolam per ml of plasma, and the variation of identical samples is 7 per cent or less. The method was used in a study of six females who received single intravenous doses of midazolam for purposes of anesthetic induction prior to minor gynecologic procedures. Mean (+/- SE) kinetic variables for midazolam were: volume of central compartment, 0.37 (+/ 0.06 l/kg; total volume of distribution, 1.72 (+/- 0.05) l/kg: initial distribution half-life, 7.2 (+/- 1.6) min; elimination half-life, 2.5 (+/- 0.2) h; total clearance, 8.1 (+/- 0.52) ml.min-1.kg-1.

Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex.

Twenty-two healthy volunteers aged 20–78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7–14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P < 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P < 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P < .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 mil ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.

Reduced quinidine clearance in elderly persons

The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

The effects of Fab fragments of high-affinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10(10) M(-1) as determined by equilibrium dialysis. Rapid second-order association kinetics (k(f) = 3.7 x 10(6) M(-1) per s) and slow dissociation kinetics (k(r) = 1.9 x 10(-4) per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/kg digitoxin intravenously developed ventricular tachycardia after 23+/-4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+/-36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+/-3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+/-4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54+/-16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135 and 118 h by radioimmunoassay and [(3)H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t((1/2)) 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise lethal digitoxin toxicity, and are capable of reducing the plasma half-life and accelerating urinary excretion of digitoxin.