Physiological basis of multicompartmental models of drug distribution.

Although most pharmacokinetic studies are conducted in normal subjects, their clinical utility depends on the reliability with which the results can be extrapolated to patients. This reliability can be improved by increased understanding of how drug absorption and disposition mechanisms are affected by physiological changes or by disease. In recent years, important insight has been gained regarding the effects of altered renal function on drug elimination by the kidneys. There has also been considerable progress in defining the interaction of hemodynamic and metabolic factors that affect the hepatic elimination of drugs. Although comparatively little progress has been made in elucidating the underlying basis of changes in the rate and extent of drug distribution, Arthur Atkinson and colleagues analyse methods of compartmental pharmacokinetic analysis that may provide physiological insight into the factors affecting drug distribution.

Torsade de pointes induced by N-acetylprocainamide.

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.

Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women.

Sera from 10 subjects in the third trimester of pregnancy and from 10 nonpregnant women were studied to elucidate the mechanism underlying decreased theophylline protein binding during pregnancy. Consistent with the physiologic hypoalbuminemia of pregnancy, serum albumin concentrations averaged only 3.2 +/- 0.3 gm/dl (+/- SD) in pregnant subjects, compared with 4.4 +/- 0.3 gm/dl in control subjects (p less than 1 x 10(-6], and this was the main cause of decreased theophylline binding. Saturation binding studies indicated a single class of theophylline binding sites. Theophylline binding capacity (N) was greater in pregnant (N = 4.3 +/- 1.0) than in nonpregnant (N = 3.3 +/- 0.4) subjects, but binding affinity (ka) averaged only 227 +/- 69 (mol/L)-1 in pregnant subjects, compared with 303 +/- 44 (mol/L)-1 in control subjects (F2,17 = 4.26; p = 0.032). At a theophylline plasma concentration of 10 micrograms/ml, the combined effects of hypoalbuminemia and lowered ka would reduce theophylline binding to 31% +/- 3% in pregnant women, compared to 39% +/- 3% in nonpregnant control subjects (p less than 1 x 10(-5]. Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy-associated decrease in theophylline binding.

Theophylline pharmacokinetics in pregnancy.

Theophylline pharmacokinetics were studied serially in five women during and after pregnancy. Theophylline protein binding was reduced to 11.1% +/- 4.7% (P less than 0.01) and 13.0% +/- 5.9% (P less than 0.01) during the second and third trimesters of pregnancy, respectively, compared with 28.1% +/- 2.8% when the patients were more than 6 months postpartum. Similar comparisons indicate that theophylline distribution volume and elimination t1/2 were increased from 30.7 +/- 4.4 L and 262 +/- 57 minutes to 36.8 +/- 4.2 L (P less than 0.05) and 389 +/- 73 minutes (P less than 0.01) in the third trimester of pregnancy. In the second and third trimesters, intrinsic nonrenal clearance was reduced to 0.82 +/- 0.25 ml/min X kg (P less than 0.05) and 0.67 +/- 0.18 ml/min X kg (P less than 0.01) compared with a remote postpartum value of 1.25 +/- 0.37 ml/min X kg. However, these reductions were offset by increases in theophylline intrinsic renal clearance so that apparent reductions in the overall unbound clearance of this drug did not reach statistical significance either during pregnancy or in the early postpartum period.

Effect kinetics of N-acetylprocainamide-induced QT interval prolongation.

We attempted to correlate clinical response with the effects of N-acetylprocainamide (NAPA) on the QT interval in five patients with stable chronic ventricular arrhythmias. A 15 mg/kg dose of NAPA was administered and a pharmacokinetic-pharmacodynamic model was used to relate plasma NAPA concentrations to changes in corrected QT interval (QTc). NAPA volume of distribution, elimination clearance, and elimination half-life averaged 1.37 +/- 0.19 L/kg, 174 +/- 63 ml/min, and 8.2 +/- 1.4 hours, respectively (mean +/- SD), and NAPA renal clearance averaged 1.9 +/- 0.6 times creatinine clearance. QTc prolongation was characterized by a linear-effect model in the first four patients and averaged 2.4 msec for every microgram per milliliter NAPA in a hypothetic biophase. QTc prolongation in patient 5 was exaggerated and was analyzed with an Emax model. Nonetheless, NAPA did not control this patient's arrhythmia. Conversely, patient 1 subsequently developed torsade de pointes even though QTc prolongation in this patient was comparable to that in patients 2 through 4, who responded satisfactorily to NAPA. We conclude that QT interval changes during initial NAPA administration do not reliably predict subsequent clinical response.

N-Acetylprocainamide pharmacokinetics in functionally anephric patients before and after perturbation by hemodialysis.

NAPA pharmacokinetics were studied in 6 functionally anephric patients. Distribution and nonrenal elimination of this drug were found to be the same as in individuals with normal renal function but renal clearance was reduced, resulting in a mean elimination t 1/2 of 41.9 hr (6.2 hr in normal subjects). Renal clearance of NAPA correlated well with ClCr. Dialysis removed NAPA from both red blood cells and plasma and increased ClT approximately fourfold. Dialysis itself resulted in a 77% reduction in ClS that limited the total amount of NAPA removed by this procedure. This reduction in ClS was sustained for at least 3 hr after dialysis and attenuated rebound in plasma NAPA concentrations.

Kinetics of N-acetylprocainamide deacetylation.

The kinetics of N-acetylprocainamide (NAPA) deacetylation to procainamide (PA) were determined in a normal subject using NAPA-13C, labeled in the acetyl group. The deacetylation clearance of NAPA (ClD) was found to be 6.5 ml/min whereas total NAPA elimination clearance was 231 ml/min, so that 2.8% of the administered NAPA-13C was metabolized by deacetylation. This estimated of ClD was shown to be representative of the rate of NAPA deacetylation in four patients on long-term NAPA therapy. Steady-state [PA]/[NAPA] ratios averaged 0.024, but would be expected to rise to 0.057 if functionally anephric patients were treated with NAPA. Despite reports that patients with the PA-induced systemic lupus erythematosus-like reaction have had symptomatic and immunologic remission when switched to NAPA, the demonstration that NAPA is deacetylated to PA indicates that the apparently greater immunologic safety of NAPA may be relative rather than absolute.

Acute tolerance to cocaine in humans.

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half-life of 31 +/- 13 (mean +/- SD) minutes toward a plateau at 33% +/- 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration-effect relationship.

Kinetics of cocaine distribution, elimination, and chronotropic effects.

The pharmacokinetics of cocaine were studied in five subjects with histories of drug abuse who were otherwise healthy. A two-compartment system was used to model the distribution kinetics of the drug. The steady-state volume of distribution averaged 131.8 L or 1.96 L/kg, elimination clearance was 2.10 L/min, and the t 1/2 was 48 minutes. Cocaine concentrations in a hypothetic biophase were estimated to correlate the chronotropic effects of this drug with its pharmacokinetics. The experimentally determined kinetic parameters indicate that the peak chronotropic effect would occur 7.3 minutes after intravenous bolus injection of cocaine, and that biophase cocaine concentrations would initially accelerate the heart rate by 0.3 bpm for each 1 ng/ml. The kinetic analysis also demonstrated that the chronotropic effects of cocaine decline more rapidly than either plasma levels or biophase concentrations. This progressive attenuation in intensity of the chronotropic effect of a given biophase cocaine concentration could be modeled as a first-order process and is compatible with either the intervention of homeostatic reflex mechanisms or the phenomenon of acute tolerance.

Kinetics of theophylline transfer to breast milk.

Investigation of three nursIng women given theophylline intravenously defined the kinetics of theophylline transfer into breast milk. In each subject, R was constant, with no significant delay between the attainment of peak plasma and peak milk concentrations. The amount of theophylline eliminated into milk was equal to the product of R, milk volume, and the simultaneous maternal plasma concentration. The data indicate that theophylline cumulation to toxic concentrations should not occur in most breast-fed infants of asthmatic women treated with appropriate doses of theophylline.

Kinetics of epsilon-aminocaproic acid distribution, elimination, and antifibrinolytic effects in normal subjects.

The kinetics of epsilon-aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10-gm iv dose. Steady-state distribution volume averaged 30.01 or 0.39 l/kg. Mean elimination t 1/2 was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet-rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half-maximal inhibition (IC50) of 63 +/- 19.7 microgram/ml. This agrees with the value of 0.55 mM or 72 microgram/ml that has been reported for the dissociation constant of the EACA-plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.

Simultaneous analysis of inulin and 15N2-urea kinetics in humans.

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2-urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three-compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 +/- 0.009 L/kg (+/- SD) for inulin and of 0.670 +/- 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient-surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 +/- 0.49 L/min and was similar to dual-beam Doppler measurements of cardiac output (5.47 +/- 0.40 L/min).

Pharmacokinetics of N-acetylprocainamide in patients profiled with a stable isotope method.

N-Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA-13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 +/- 2.6 L (mean +/- SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady-state distribution volume of 1.45 +/- 0.09 L/kg were similar to normal subject values. The least-squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age-associated decrease. The oral NAPA dose was 78.0% +/- 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r = 0.89, p = 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.

Assay of stable isotope labelled urea in biological fluids by selected ion monitoring.

A selected ion-monitoring method, incorporating an internal standard, was developed to allow the direct and simultaneous measurement of stable isotope-labelled urea and unlabelled urea concentrations in biological specimens. After cyclization of urea with malonaldehyde bis(dimethylacetal) to form 2-hydroxypyrimidine, the volatile heptafluorobutyryl derivative was made in a two-step process utilizing a trimethylsilyl intermediate. The internal standard, 4-methyl-2-hydroxypyrimidine, was found to be stable under the cyclization conditions. The structures of the internal standard and urea derivatives were confirmed by electron impact and chemical ionization mass spectrometry. This method was applied to the measurement of [15N2]urea concentrations in dog plasma.

Urinary excretion of ecgonine methyl ester, a major metabolite of cocaine in humans.

In this study, cocaine, benzoylecgonine, and ecgonine methyl ester excretion in urine was measured after intravenous and intranasal administration of cocaine at 16, 32, 48, and 96 mg doses to healthy cocaine users. Ecgonine methyl ester and cocaine were analyzed by gas chromatography/mass spectrometry. Benzoylecgonine was measured by immunoassay (EMIT) and liquid chromatography. Urinary ecgonine methyl ester accounted for 26 to 60% of the cocaine dose. Ecgonine methyl ester had an elimination halflife of 4.2 hr, compared with 5.1 hr for benzoylecgonine. These results indicate that ecgonine methyl ester accounts for most of the previously unidentified urinary metabolic products of cocaine. The time course of ecgonine methyl ester excretion is such that its detection can substitute for benzoylecgonine detection as a marker of cocaine use.

A kinetic model of benzoylecgonine disposition after cocaine administration in humans.

Cocaine (C) and benzoylecgonine (BZ) plasma levels and urinary excretion rate data from a series of intravenous cocaine studies were used to develop a kinetic model for C and BZ, with the main objective of characterizing BZ disposition. Kinetic analyses were made with the CONSAM 30 computer program. Under assumptions of the model, calculated parameters indicated a BZ distribution volume of 50 L, a half-time for BZ formation of 1.9 h and a BZ excretion half-time of 4.7 h. The model may eventually provide a basis for interpretation of analytical data on isolated samples of plasma or urine.

Urinary excretion of cocaine, benzoylecgonine, and ecgonine methyl ester in humans.

The excretion kinetics of cocaine (C) and its two major metabolites, benzoylecgonine (BZ) and ecgonine methyl ester (EME), were determined by collecting all urine for 30 h from 5 cocaine users (subjects C, D, E, F, and G) given bolus doses followed by exponential cocaine infusions that delivered doses of 253 (subject C), 444 (subjects D, E, and F), and 700 mg (subject G). Plasma cocaine, urine cocaine, BZ, and EME were measured by gas chromatography, with a nitrogen detector. Elimination half-times for EME and BZ, estimated from semilog plots of excretion rates vs. time, averaged 3.1 and 4.5 h respectively, in agreement with our previous report. Urinary recovery in D, E, and F was 27-41% of the dose, with 14-17% as BZ, 12-21% as EME, and 2% as cocaine. Subject C excreted very little EME--5-6-fold less than the mean for the other subjects and amounting to only 3% of the dose. Cocaine disposition in subject G, who received the largest dose and attained plasma levels of 3000 ng/mL, showed some characteristics of a nonlinear process.

Ecgonine methyl ester, a major metabolite of cocaine.

Most assays for the identification of cocaine use are aimed at detection of benzoylecgonine, a major urinary metabolite. Gas chromatography assays require derivatization of benzoylecgonine. Recently, ecgonine methyl ester (methylecgonine) has been shown to be major urinary metabolite of cocaine in man after oral administration. These results indicate that ecgonine methyl ester is a prominent urinary metabolite after street use of cocaine, which primarily involves intranasal application and intravenous injection rather than ingestion. Advantages of GC/MS analysis for ecgonine methyl ester in identifying cocaine use include the ability to chromatograph it on common stationary phases without derivatization and its early elution.

Pharmacokinetics of N-acetylprocainamide.

Shortly after Dreyfus and his colleagues demonstrated that procainamide was metabolized by acetylation to N-acetylprocainamide (NAPA), Drayer, Reidenberg and Sevy reported that NAPA had antiarrhythmic activity in an animal model. We confirmed these findings and found that plasma levels of NAPA were high enough to warrant consideration in managing patients requiring procainamide therapy. However, the actual impetus for developing NAPA as an antiarrhythmic drug in its own right was provided by the initial studies of NAPA pharmacokinetics in normal subjects. In these studies, we showed that NAPA has an elimination-phase half-life that is more than twice as long as procainamide and suggested that patient compliance and arrhythmia suppression might be improved if NAPA were used to circumvent the inconvenience of the frequent dosing schedule that has been recommended for procainamide. From the standpoint of managing individual patients with NAPA, the pharmacokinetics of this drug continue to provide the scientific basis for designing dose regimens that will have maximal antiarrhythmic efficacy and minimal toxicity. This review summarizes the salient features of NAPA pharmacokinetics and outlines an approach for individualizing therapy with this drug.

Comparison of the pharmacokinetic and pharmacodynamic properties of procainamide and N-acetylprocainamide.

Although procainamide (PA) has been widely used to treat patients with both ventricular and supraventricular arrhythmias since 1951, more than twenty years elapsed before N-acetylprocainamide (NAPA) was identified as a major PA metabolite and shown in PA-treated patients to have plasma concentrations generally equaling or being 2 to 3 times greater than those of the parent drug. Numerous investigations have been conducted since then to characterize the pharmacokinetics and pharmacodynamics of NAPA and to compare these properties with those of PA. Salient differences have been that the elimination half-life of NAPA is 2.5 times that of PA, even when renal function is normal; that NAPA has a spectrum of electrophysiologic action that differs from PA in that NAPA only prolongs action potential duration; and that NAPA is less likely than PA to cause a syndrome resembling systemic lupus erythematosus. Although these properties have provided an impetus for the development of NAPA as an antiarrhythmic drug in its own right, emphasis is placed in this review on the implications of these findings for individualizing PA therapy.