David J. Greenblatt

Importance of Protein Binding for the Interpretation of Serum or Plasma Drug Concentrations

Abstract: The extent of drug binding to plasma protein does not influence the concentration of unbound drug in plasma at steady state but does influence the interpretation of total drug concentrations. An increase in free fraction (reduction in the extent of binding) decreases the therapeutic and toxic ranges for total drug concentrations. Conversely, a reduction in free fraction (increase in the extent of binding) increases these ranges. Laboratories generally measure total rather than unbound drug concentrations, and clinicians must use caution in interpreting these total drug concentrations in clinical situations where the extent of binding of extensively bound drugs may be altered. Free drug serum or plasma concentrations are inherently more reliable indices of the intensity of drug action than are total concentrations. Methodology for routine measurement of free concentration is becoming available and should ultimately be utilized for therapeutic monitoring of drugs that are highly bound to protein.

Clinical pharmacokinetics of lorazepam

Eight healthy male subjects received single 2‐mg oral doses of lorazepam containing 24 uLCi Img of 2‐14C‐lorazepam. Multiple venous blood samples were drawn during the .first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first‐order half‐life of 15 min. The peak plasma concentration was 16.9 ng Iml, measured in the pooled sample drawn 2 hr after the dose. This corresponded to the time at which clinical eflects appeared to be maximal. The apparent elimination half‐life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.

Clinical Pharmacokinetics of Lorazepam. III. Intravenous Injection. Preliminary Results

Four healthy male volunteers received 5 mg lorazepam as a single intravenous injection. Concentrations of lorazepam and its glucuronide metabolite were determined in multiple venous blood samples drawn during the 48 hours after dosing and in all urine collected during 96 hours after the dose. Mean pharmacokinetic parameters for lorazepam were: apparent elimination half-life, 13.2 hours; volume of distribution, 0.84 liter/kg; total clearance, 55.3 ml/min. Lorazepam glucuronide, the major metabolic product of lorazepam, promptly appeared in blood, reached peak levels within 6 hours of the dose, then declined in parallel with the parent compound. A mean of 69 per cent of the dose was recovered in urine as lorazepam glucuronide.

Impairment of digoxin clearance by coadministration of quinidine.

Abstract: Seven healthy volunteers received a single 1.0‐mg dose of intravenous digoxin in a drug‐free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half‐life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min‐kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long‐term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P < 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.

Comparative Protein Binding of Diazepam and Desmethyldiazepam

Abstract: The extent of plasma protein binding of diazepam (DZ) and its major metabolite, desmethyldiazepam (DMDZ), was determined by equilibrium dialysis in plasma samples drawn from 62 nonfasting unheparinized volunteers aged 20 to 85 years. The free fraction for diazepam averaged 1.48 per cent (range 0.85 to 2.30 per cent) and increased with age (r = 0.33). Desmethyldiazepam also was extensively bound. The mean free fraction was 2.97 per cent (range 1.78 to 5.28 per cent) and increased with age (r = 0.27). Free fractions for both diazepam and desmethyldiazepam were negatively correlated with plasma albumin concentration (r = −0.17 and − 0.39). However, age, sex, and albumin explained only a small proportion of variability in free fraction for either compound. Free fraction for desmethyldiazepam always exceeded that for diazepam, and the two were correlated (r = 0.32). Thus, at any given total plasma concentration, the unbound concentration of desmethyldiazepam will exceed that of diazepam.

Is volume of distribution at steady state a meaningful kinetic variable

Abstract: Pharmacokinetic volumes of distribution (Vd) are commonly calculated either by the steady‐state method (Vdss) or the area method (Vdarea). Vdss is traditionally perceived as the least biased and most reliable indicator of the extent of distribution, but Vdss in fact has far greater practical and theoretical limitation than does Vdarea. After single doses or multiple discrete doses of a drug, Vdarea correctly relates plasma concentration to amount of drug in the body at all times after distribution equilibrium is attained. Vdss, on the other hand, is a correct proportionality constant only during continuous intravenous infusion or at a single instant in time after discrete dosing. Furthermore, calculated values of Vdss are strongly dependent on the precise configuration of the initial distributional phase of the plasma concentration curve, which may be difficult or impossible to delineate because of variance arising from methodologic artefacts or unexplained causes. Such variance can lead to large nonphysiologic within‐ and between‐individual variability in Vdss Vdarea, on the other hand, is relatively independent of artefactual changes in the initial distribution profile. Finally, experimental observations indicate that elimination depends physiologically on distribution in the absence of changes in clearance, not the reverse. The relation of distribution and elimination holds whether the steady‐state method or the area method is used to calculate Vd. Thus, Vdarea is a more reliable and generally valid descriptor of the extent of drug distribution than is Vdss.

Zolpidem Pharmacokinetic Properties in Young Females: Influence of Smoking and Oral Contraceptive Use

Sixteen normal healthy female volunteers, ages 22 to 42 years, participated in this study to determine the pharmacokinetic characteristics of zolpidem and the influence of oral contraceptives and smoking. Five of the volunteers were cigarette smokers, and 8 were on oral contraceptive preparations (OCP). All subjects received a 5 mg oral dose of zolpidem tartrate, followed by multiple blood samples that were assayed by HPLC with fluorescence detection. Among all subjects, mean apparent oral clearance was 376 ml/min (5.8 ml/min/kg), elimination half‐life was 2.4 hours, and maximum serum zolpidem concentration was 60 ng/ml. Clearance was higher (445 vs. 345 ml/min) and half‐life was shorter (1.8 vs. 2.7 h) in smokers than nonsmokers, although the differences were not statistically significant. Likewise, zolpidem clearance was higher and half‐life shorter in women using OCP, but differences were not significant. Differences in zolpidem kinetics associated with smoking may be explained by the small contribution of cytochrome P450‐1A2 to net clearance of zolpidem. In any case, the differences were quantitatively small and not likely to be ofclinical importance.

Effect of Magnesium—Aluminum Hydroxide and Kaolin—Pectin on Absorption of Digoxin from Tablets and Capsules

Abstract: Twelve healthy fasting volunteers received two 0.2‐mg digoxin capsules or tablets with 60 ml water, 60 ml Maalox, or 60 ml Kaopectate in a randomized, single‐dose, six‐way crossover study. Concentrations of digoxin in multiple plasma samples and in all urine collected during the 24 hours after each dose were determined by radioimmunoassay. Compared to the water treatment, administration of both tablets and capsules with Maalox or Kaopectate reduced the peak digoxin plasma concentrations but did not significantly influence the time of peak concentration. Neither Maalox nor Kaopectate influenced the area under the 24‐hour plasma concentration—time curve for either tablets or capsules. However, 24‐hour urinary recovery of digoxin from tablets tended to be reduced by Maalox and Kaopectate; this was not the case with capsules. Digoxin capsules may have an advantage over currently available tablets in clinical situations requiring digoxin coadministration with nonabsorbable gastrointestinal preparations.

Clinical Pharmacokinetics of Lorazepam. IV. Long‐Term Oral Administration

Fifteen healthy male volunteers received long-term daily treatment with oral lorazepam at doses as high as 10 mg per day for a period of 26 weeks. Steady-state plasma concentrations of lorazepam and its glucuronide metabolite were measured in all subjects at least every two weeks. At daily doses of 6 mg per day, the mean steady-state lorazepam level was 88 ng/ml and that of lorazepam glucuronide was 170 ng/ml. Mean levels among seven subjects who received 10 mg per day were 164 and 266 ng/ml, respectively. Lorazepam concentrations fluctuated from week to week despite constant dosage, but there was no evidence of systematic variation. Mean steady-state lorazepam levels were highly correlated with daily dose in mg/kg, but were not related to age. Lorazepam was not detected in any plasma samples drawn one week after discontinuation of treatment.

Intravenous digoxin as a bioavailability standard

In a recent publication in this JOURNAL, Greenblatt and associates3 recommended that the “administration of digoxin by slow infusion is preferable as an intravenous standard in bioavailability testing” as opposed to a rapid intravenous injection. While we do not necessarily disagree with this conclusion, we do disagree with the reasons cited in their publication to support this contention. Because of the likely influence an article such as this may have on federal regulatory procedures, we would like to express our alternative viewpoints as related to their study.