Milo Gibaldi

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.

The mechanism of the interaction between amiodarone and warfarin in humans

Amiodarone decreased the total body clearance of both (R)‐ and (S)‐warfarin in normal subjects but did not change volumes of distribution. Warfarin excretion products were quantified and clearance and formation clearance values calculated. Amiodarone and metabolites inhibited the reduction of (R)‐warfarin to (R,S)‐warfarin alcohol‐1 and the oxidation of both (R)‐ and (S)‐warfarin to phenolic metabolites. Inhibition of warfarin hydroxylation by amiodarone in human liver microsomes was compared with the in vivo results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor of the cytochrome P450 catalyzed oxidation of both enantiomers of warfarin, but the metabolism of (S)‐warfarin is more strongly inhibited than that of (R)‐warfarin. These data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin are coadministered is attributable to inhibition of P4502C9, the isozyme of P‐450 primarily responsible for the conversion of (S)‐warfarin to its major metabolite, (S)‐7‐hydroxywarfarin.

Food, splanchnic blood flow, and bioavailability of drugs subject to first-pass metabolism.

There has been considerable interest in the past fifteen years in determining the influence of food and diet on gastrointestinal drug absorption. Welling21 has recently presented a comprehensive and critical review of these efforts. In general, food reduces the absorption rate of drugs from the gastrointestinal tract but in most instances has little influence on the extent of absorption. Such an effect is clinically significant for sedative‐hypnotics and for other drugs where a prompt response is desired but is probably of little concern in most other cases. On the other hand, food has been found to substantially reduce the extent of absorption of certain drugs, including many antibiotics. This type of food effect often occurs with drugs with poor permeability characteristics that are incompletely absorbed even by fasting patients. Continual administration of such drugs with meals would result in lower steady‐state drug concentrations in plasma than would be found were the drug to be given under fasting conditions.

Drug distribution and pharmacologic effects

Drugs which move relatively slowly in and out of body “compartments” thereby confer pharmacokinetic characteristics of a multicompartment system and elicit a considerably different time course of pharmacologic effect than do drugs which are distributed in the body extremely rapidly. The time course of pharmacologiC effects in multicompartment systems is considered here as a function of dose and site of action and duration of repetitive dosings. The durationdose and intensity‐time patterns thus obtained are consistent with the results of clinical studies. An appreciation of these relationships should be helpful in designing effective and safe dosage regimens.

Pulmonary Disease and Drug Kinetics

SummaryA number of examples of altered drug disposition in patients with respiratory disease have been reported. These reports have been analysed in terms of absorption, distribution and elimination. The changes have been examined mechanistically in light of the pathophysiology of respiratory disease and the known influence of these physiological parameters on drug disposition. Our analysis has included in vivo and in vitro data from laboratory animals in addition to appropriate data from humans.Acute hypoxaemia appears to decrease intrinsic hepatic clearance while chronic hypoxia appears to increase intrinsic clearance. The free fraction of some bases is decreased in plasma taken from patients with chronic hypoxaemia and this change can interact with changes in intrinsic metabolic activity. Blood gas disturbances also can affect drug disposition by decreasing hepatic and renal perfusion.Cor pulmonale has not been linked to altered drug disposition, except in the case of theophylline. However, this pathophysiological condition may be equivalent to congestive cardiac failure through diminished hepatic and renal perfusion.The marked reduction (approximately 50%) in theophylline clearance documented in some asthmatic patients may reflect protein binding changes, a paradoxical response of metabolic pathways to hypoxaemia, or other as yet unidentified processes.It is apparent that respiratory disease significantly changes drug disposition through a number of interacting mechanisms. These have not been adequately studied to provide a basis for clinical dosage adjustment, however, general principles are emerging: Drugs showing flow-dependent hepatic clearance (e.g. lignocaine/lidocaine, pethidine/meperidine, propoxyphene) and those drugs showing predominant renal clearance (aminoglycosides, digoxin) should be used with caution. Theophylline doses must be reduced on an empirical basis, as the mechanisms causing reduced clearance cannot be convincingly explained in terms of the pathophysiology of respiratory disease.The lungs must be added to the existing list of organs (liver, kidney, heart) whose dysfunction significantly affects drug disposition.

Kinetics of the elimination and neuromuscular blocking effect of d-tubocurarine in man.

A pharmacokinetic model for the distribution and elimination of d-tubocurarine in man has been evolved from plasma concentration and urinary excretion data reported previously. This model represents the body as a three-compartment linear system, with the site of action of d-tubocurarinc being located in the central compartment on the basis of available knowledge of pharmacologic effects. Relationships between dose and duration of action and between dose and durations of effects of successive fractional doses administered after a constant initial dose have been predicted by the mathematical model and are in excellent agreement with experimental results. Additional simulations have been carried out to explore the effects of other dosage regimens of clinical interest for which experimental data are not presently available.

Effect of Bile Salts on Gastric Emptying and Intestinal Transit in the Rat

Summary Orally administered bile salts, sodium taurodeoxycholate and sodium deoxycholate, decreased gastric emptying and proximal intestinal transit rate in rats. The unconjugated bile salt (sodium deoxycholate) produced inhibition of gastric emptying comparable with that produced by the conjugated derivative (sodium taurodeoxycholate) at about 0.1 to 0.2 the dose. The effects on gastric emptying appeared to be proportional to the administered dose. The second intestinal segment showed an increase in transit rate with the highest bile salt dose. With all of the doses, there was an influx of fluid into the gastrointestinal tract which appeared to be proportional to the dose of bile salt given.

Prediction of systemic availability from plasma-level data after oral drug administration.

The extent to which an orally administered dose of a drug reaches the systemic circulation intact can be defined as its systemic or physiologic availability. Determination of systemic availability usually requires that the area under the plasma concentration-time curve following oral administration be compared to the corresponding area after the intravenous administration of an equal dose of the drug being studied. However, many drugs cannot be administered intravenously and availability must be determined relative to some standard oral dosage form such as an aqueous solution. Although the test dosage form may have a relative availability of loo%, its systemic availability may be substantially less if the drug under study is subject to appreciable metabolism on its initial pass through the liver. Therefore, it would be desirable to be able to predict the extent to which an orally administered drug reaches the systemic circulation from plasma concentration-time data. Equations have been developed to estimate the extent to which an orally administered drug is metabolized on its first-pass through the liver (Gibaldi, Boyes & Feldman, 1971). These investigators have pointed out that the following relation may be used to predict the maximum fraction of an orally administered drug reaching the systemic circulation.

Effect of antacids on pH of urine

To determine the effect of regular administration of usual doses of several antacids for 7 day periods on urine pH, measurements of urine pH were carried out daily on 11 healthy subjects during regular use of antacids and during control periods. On the average, suspensions of aluminum hydrOXide and dihydroxyaluminum glycinate had no significant effect on urine pH. Magnesium hydroxide and calcium carbonate‐glycine suspension increased urine pH by 0.4 to 0.5 U, while aluminum and magnesium hydroxide suspension increased pH by 0.9 U. The increase in urine pH was inversely proportional to the urine pH during the control periods. Regular administration of certain antacids can increase urine pH sufficiently to have pronounced effects on the kinetics of elimination of certain acidic and basic drugs.

Biopharmaceutic influences on the anticholinergic effects of propantheline.

With reduction of salivary flow rate as an index of anticholinergic response, 3 subjects manifested demonstrable effects shortly after ingestion of 15‐mg doses of propantheline in conventional tablets. Ingestion of this dose immediately after a standardized breakfast substantially reduced the anticholinergic effects. In 1 subject, a dose‐response relationship was noted after 15 mg and 30 mg doses under both fasting and fed conditions, but at each dose level the influence of food was clear. Administration of a 30‐mg dose of propantheline in a commercially available “prolonged‐acting” tablet induced little if any anticholinergic effects; in 2 subjects, marginal but fleeting indications of salivary suppression were noted about 4 hr after ingestion, while no effects were observed in the third subject (even after 2 “prolonged‐acting” tablets).