Methadone binding to orosomucoid (alpha 1-acid glycoprotein): determinant of free fraction in plasma.

The distribution of basic drugs in blood differs qualitatively from that of acidic drugs. The binding of racemic, d-methadone, and l-methadone to human plasma and isolated protein fractions was studied by equilibrium dialysis at 37 degrees. In plasma samples from 29 healthy subjects free fraction of dl-methadone was (mean% +/- SD) 10.62 +/- 1.43. There were significant variations among subjects (p less than 0.001). The free fraction of the d-isomer was 9.24 +/- 1.61% and of the l-isomer, 12.44 +/- 1.53%. Plasma albumin concentration and degree of binding do not correlate, but in normal hypoalbuminemic subjects the free fraction of dl-methadone correlates negatively with the concentration of alpha 1-acid glycoprotein (alpha 1-AGP), an acute-phase reactant protein. Percentage dl-methadone bound to purified human serum albumin (HSA) (4.1 mg/dl) was 36.60% (mean +/- SD). Isolated alpha 1-AGP bound dl-methadone more avidly. As the alpha 1-AGP increased from 0.05 to 2.0 gm/l, free fraction fell from 92.40% to 8.80%. Addition of alpha 1-AGP (0.05 to 2.0 gm/l) to a physiologic concentration of purified HSA or to whole plasma progressively increased methadone binding. In eight monozygotic twin pairs, within-pair differences in binding of dl-methadone were less than in eight dizygotic twin pairs. Less than 20% of naloxone, codeine, morphine, heroin, pentazocine, and diphenoxylate bound to alpha 1-AGP. Elevations of alpha 1-AGP that occur in a variety of diseases may alter the kinetic and pharmacologic activity of methadone.

Disease-induced changes in the plasma binding of basic drugs.

The plasma binding of basic (cationic) drugs differs from that of the more completely studied acidic drugs. Basic drugs associate with a number of plasma constituents. alpha 1-Acid glycoprotein, lipoprotein, and albumin all appear to play an important role in the binding of most of these drugs. Acidic drugs bind largely to albumin. The variation in plasma albumin is relatively narrow and is almost always in the direction of decreased concentrations. alpha 1-Acid glycoprotein and lipoproteins show large fluctuations due both to physiological and pathological conditions. Decreases and increases in concentration have been observed. Associated with these changes in binding proteins, both decreases and increases in plasma binding of basic drugs have been recorded. Increased binding with disease appears to be virtually unique to basic drugs. The implications of these newly described disease-induced increases in plasma binding have yet to be explored. With the limited information in hand the following consequences are predicted. Increased binding will tend to decrease the volume of distribution of total (bound plus free) drug. The clearance will be unchanged or decreased depending upon the initial clearance of the drug and the avidity of the protein binding. As the half-life depends upon both clearance and volume of distribution, changes in it will be variable, depending upon changes in these two parameters. It is predicted that the area under the free drug plasma concentration-time curve will decrease with increasing binding after an intravenous dose while it will be unchanged after an oral dose. The relationship of total drug plasma concentration to free drug concentration will change with changes in binding. Thus plasma concentration monitoring of drug therapy by use of total drug concentrations will be inaccurate in situations in which large variations in binding occur. Misinterpretations of both therapeutic monitoring and pharmacokinetics studies in disease states with altered binding are likely unless these changes are appreciated.

Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma alpha1 acid glycoprotein.

To assess the importance of disease-induced increases in plasma concentrations of alpha1 acid glycoprotein (an acute-phase plasma protein that binds cationic drugs), we determined binding of propranolol in plasma from 53 patients and 25 healthy volunteers. Binding was increased in 10 patients with Crohn's disease (P less than 0.002), nine with inflammatory arthritis (P less than 0.002) and eight with chronic renal failure with superimposed inflammatory disease (P less than 0.01) as compared with healthy controls. The plasma binding of control subjects did not differ from that of 12 patients with chronic hepatic disease (P greater than 0.45) or 14 with uncomplicated renal failure (P greater than 0.80). Chlorpromazine binding, determined in 60 subjects, yielded similar results. Percentage of free drug and alpha1 acid glycoprotein concentration were inversely correlated (r = -0.77 with propranolol, P less than 0.001, and r = -0.69 with chlorpromazine, P less than 0.001). Increases in plasma protein binding in patients with inflammatory disease appear mediated by increases in alpha1 acid glycoprotein concentration, which may influence drug kinetics.

Antihypertensive responses to spironolactone in normal renin hypertension.

The antihypertensive effect of spironolactone was studied in 20 patients with essential hypertension and normal stimulated peripheral renin activity (PRA). Single-blind 8-wk treatment periods of placebo, 100, 200, and 400 mg spironolactone were used in consecutive order. Average supine and erect blood pressures were lower than placebo values at the end of each treatment. A prominent orthostatic effect was observed. Changes in blood pressure were not related to changes in body weight, PRA, or blood urea nitrogen. A larger proportion (50%) of patients had a more normal erect diastolic pressure at the end of 400 mg/day than at the end of 100 mg/day (20%), but the response to 400 mg/day could not be predicted from the responses to lower doses. Larger doses of spironolactone were predictably associated with rises in serum potassium, PRA, and aldosterone excretion. Adverse effects were absent during therapy with 100 mg/day but were frequent during 200--400 mg/day. Although there are no apparent advantages in increasing spironolactone from 100 to 200 mg/day in this group of patients with normal renin hypertension, increasing the dose to 400 mg/day resulted in better blood pressure control with more frequent adverse effects.

Plasma protein binding of basic drugs. I. Selective displacement from alpha 1-acid glycoprotein by tris(2-butoxyethyl) phosphate.

The protein binding of a number of basic drugs has been shown to be inhibited when blood is collected in Vacutainer tubes. We found that the plasticizer tris(2-butoxyethyl) phosphate (TBEP), present in plasma collected in Vacutainers, was a potent inhibitor of alprenolol and imipramine protein binding. Its concentration in the plasma could quantitatively explain the displacement phenomenon. Alprenolol binding to a solution of a physiologic concentration (0.67 gm/L, 0.015 mM) of alpha 1-acid glycoprotein (orosomucoid) was decreased from 75% to 16% by addition of 10 microgram/ml (0.026 mM) of TBEP, while imipramine binding was decreased from 69% to 13%. Alprenolol and imipramine binding to albumin and lipoproteins was virtually unchanged by TBEP. Due to its selective effect on binding to alpha 1-acid glycoprotein, TBEP may be a useful tool for studying plasma protein binding of basic drugs.

Plasma protein binding of basic drugs. II. Importance of alpha 1-acid glycoprotein for interindividual variation.

The protein binding of two basic drugs, alprenolol and imipramine, and the acidic drug, naproxen, was determined in plasma obtained from 23 healthy subjects. A 2-fold variation was found between individuals in the free fraction of the two bases, while the range was even greater with naproxen. The free fraction correlated with the plasma concentration of alpha 1-acid glycoprotein for alprenolol (r = -0.75, p less than 0.001) and imipramine (r = -0.78, p less than 0.001), while there was no correlation for naproxen (r - 0.24, p greater than 0.1). This confirms recent experiments which showed that isolated alpha 1-acid glycoprotein avidly bound both alprenolol and imipramine. Drug binding, however, did not correlate with albumin concentration, although experiments with isolated albumin demonstrated its unusually high affinity for naproxen.

Effect of phenobarbital on the disposition of intravenous theophylline.

The disposition of intravenous doses of theophylline was determined in normal male subjects before and after treatment with phenobarbital 2 wk. Although there was some variation in disposition of the 2 drugs, there were no significant effects of phenobarbital on theophylline kinetics. We conclude that theophylline dosage need not be altered during concomitant administration of phenobarbital.

Theophylline disposition in patients with hepatic cirrhosis.

To determine the role of liver dysfunction in theophylline toxicity, we administered single intravenous doses of the drug to nine patients with cirrhosis and observed its disposition over a period of 24 to 48 hours. As compared to 19 normal subjects, these patients had a prolonged plasma half-life (mean, 25.6 vs. 6.7 hours) and a decreased plasma clearance (mean, 0.042 vs. 0.062 liter[kg-1]hr-1). Volumes of distribution of theophylline in the cirrhotic patients (central-compartment volume of 0.330, and steady-state volume of distribution of 0.785 liter per kilogram) did not substantially differ from normal (0.246 and 0.508 respectively). Plasma theophylline binding in three patients with cirrhosis averaged 36.8 per cent as compared to 52.6 per cent in four normal subjects. There was no correlation between any laboratory test of liver function and the plasma theophylline half-life, except for serum albumin (r = 0.92, P less than 0.001). The variable capacity to eliminate theophylline precludes the use of usual maintenance dose schedules for bronchodilation in cirrhosis.

Theophylline kinetics in acute pulmonary edema.

Nine patients with acute cardiogenic pulmonary edema were given theophylline intravenously, and its disposition was observed over the next 24 hr. Compared to that in 19 normal subjects, these patients had prolonged plasma half-lifes (mean, 22.9 from 6.7 hr) and decreased plasma clearances of theophylline (mean, 0.041 from 0.062 L [kg-1] hr-1). The intersubject variation in these parameters was 20-fold in patients with pulmonary edema and 4-fold in normal subjects. Since the peak plasma concentrations attained and the apparent volumes of distribution were not different in the two groups, a suitable initial dose can be calculated. A loading dose of 4.5 to 5 mg/kg theophylline (6 mg/kg aminophylline) given over 20 min appears safe. Because of the great variability in the plasma clearance of this drug in patients with heart failure, plasma concentrations and toxicity would be unpredictable after repeated doses or constant infusions.

Duration of cardiac effects of timolol and propranolol.

The duration of the cardiac effects of single intravenous doses of the beta-antagonists, timolol and propranolol, was compared in 6 healthy male subjects. Timolol and propranolol were given in doses of 1 mg and 10 mg, respectively, and at specified times after their administration, beta-blockade was assessed by the reduction of maximal exercise-induced tachycardia and by the inhibition of the chronotropic and inotropic effects of isoproterenol. Inotropic effects were measured by changes in the pre-ejection period of left ventricular systole obtained from systolic time intervals. There was no statistically significant difference in the timolol and propranolol time-courses of beta-blockade. The change in exercise-tachycardia was maximal 5 min after beta-antagonist infusion but dissipated rapidly so that no statistically significant change was observed 9 hr later. The chronotropic and inotropic effects of isoproterenol were almost completely antagonized for 11/2 hr after beta-antagonist infusion, and significant beta-blockade could be demonstrated 9 hr later. There was no difference in the time-course of the negative chronotropic and inotropic effects of either beta-antagonist.

Plasma theophylline concentrations measured by high-pressure liquid chromatography.

We present a specific, sensitive high-pressure liquid-chromatographic assay for theophylline in plasma. Only 0.5 ml of plasma is required for each determination, and the lower limit of detection by this method is 0.1 mg/liter. Other xanthines and their metabolites do not interfere. This method is suitable for use in studying the pharmacokinetics of this drug in infants and children, from whom only small volumes of blood are available.

Comparison of cardiac effects of timolol and propranolol.

The cardiac effects of the beta-adrenergic blocking agent, timolol, were compared to those of propranolol after intravenous administration in 6 healthy male subjects. The effects of timolol and propranolol on maximal exercise-induced tachycardia were measured. Timolol was about ten times as potent as propranolol in antagonizing exercise-induced tachycardia. Dose-response curves to intravenous infusions of isoproterenol were obtained after three doses of each beta-antagonist. Changes in myocardial contractility were assessed by cardiac systolic time intervals and were compared to the simultaneous changes in heart rate elicited by isoproterenol. For the 6 subjects, the mean potency ratios of timolol to propranolol as an antagonist of the chronotropic and inotropic effects of isoproterenol were 13.8 (+/-0.8) and 12.7 (+/-1.0), respectively. Neither timolol nor propranolol acted more selectively on beta-receptors affecting heart rate than on those influencing contractility.

Points to remember in prescribing drugs during pregnancy.

Our knowledge of possible adverse drug effects on the fetus is quite limited. The doctor must act as the fetus' first line of defence. Mothers must be educated about the dangers of self-medication. Physicians must guard against drug administration to pregnant women unless the indications are clear and the expected benefit outweighs the possible risk to the fetus.