Tsuen Ih Ruo

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 t½ 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.

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.

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 t½ 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 ClTapproximately 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.

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.

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 < 0.01) and 13.0% ± 5.9% (P < 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 < 0.05) and 389 ± 73 minutes (P < 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 · kg (P < 0.05) and 0.67 ± 0.18 ml/min • kg (P < 0.01) compared with a remote postpartum value of 1.25 ± 0.37 ml/min · 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.

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 €‐aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10‐gm iv dose. Steady‐state distribution volume averaged 30.0 l or 0.39 l/kg. Mean elimination t½ 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 µg/ml. This agrees with the value of 0.55 mM or 72 µg/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.

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 estimate 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.

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).

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 < 1 × 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 μg/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 < 1 × 10−5). Nonesterified fatty acid concentrations were similar in both subject groups and did not contribute to the pregnancy‐associated decrease in theophylline binding.