David G. Shand

A physiological approach to hepatic drug clearance

A physiological approach has been developed recognizing that hepatic blood flow, the activity of the overall elimination process (intrinsic clearance), drug binding in the blood, and the anatomical arrangement of the hepatic circulation are the major biological determinants of hepatic drug clearance. This approach permits quantitative prediction of both the unbound and total drug concentration/time relationships in the blood after intravenous and oral administration, and any changes that may occur as a result of alterations in the above biological parameters. These considerations have led to a classification of drug metabolism based on the hepatic extraction ratio. The proposed classification allows prediction and interpretation of the effects of individual variations in drug‐metabolizing activity, route of administration, pharmacokinetic interactions, and disease states on hepatic drug elimination.

Effects of Caffeine on Plasma Renin Activity, Catecholamines and Blood Pressure

Using a double-blind, randomized, cross-over protocol, we studied the effect of a single dose of oral caffeine on plasma renin activity, catecholamines and cardiovascular control in nine healthy, young, non-coffee drinkers maintained in sodium balance throughout the study period. Caffeine (250 mg) or placebo was administered in a methylxanthine-free beverage to overnight-fasted supine subjects who had had no coffee, tea or cola in the previous three weeks. Caffeine increased plasma renin activity by 57 per cent, plasma norepinephrine by 75 per cent and plasma epinephrine by 207 per cent. Urinary normetanephrine and metanephrine were increased 52 per cent and 100 per cent respectively. Mean blood pressure rose 14/10 mm Hg one hour after caffeine ingestion. There was a slight fall and then a rise in heart rate. Plasma caffeine levels were usually maximal one hour after ingestion but there was considerable individual variation. A 20 per cent increase in respiratory rate correlated well with plasma caffeine levels. Under the conditions of study caffeine was a potent stimulator of plasma renin activity and adrenomedullary secretion. Whether habitual ingestion has similar effects remains to be determined.

Reduced β-adrenoceptor sensitivity in the elderly

The effect of age on sensitivity to both isoproterenol and propranolol has been investigated in 27 male volunteers aged 21 to 73 yr. The dose of isoproterenol (given as a rapid intravenous injection) required to increase the resting heart rate by 25 bpm (I25) increased with age. The I25 was repeated during an intravenous infusion of propranolol and the dose ratio (I25 after propranolol divided by the control I25) determined. This was related to the concentration of free propranolol in plasma. It was found that the effectiveness of any given free concentration diminished progressively with age. These data are consistent with a diminished responsiveness of the β‐adrenoceptor to both agonist and antagonist drugs with advancing years.

Plasma propranolol levels in adults With observations in four children

Plasma levels of the f3‐adrenergic‐blocking drug, propranolol, have been measured fluorometrically in man after oral and intravenous administration. Following oral administration, peak plasma levels in 5 sub/ects varied sevenfold, while, after intravenous administration, levels in the same sub/ects varied only twofold, indicating considerable variability among individuals in the amount of drug reaching the systemiC circulation after oral administration. However, plasma levels were relatively constant in sub/ects given repeated, single doses. The plasma half‐life of the drug was 2.3 hours after intravenous administration. A plasma half‐life of 3.2 hours was found after oral administration; its greater duration was attributed to continuing absorption. After intravenous administration, the rate of decline of the levels of propranolol in the plasma was biexponential, and the volume of distribution during the late phase of elimination was found to be about 150 liters, indicating concentration of the drug in the tissues. The drug was administered orally to 4 children at dose levels calculated on the basis of body weight and on the basis of body surface area. It was found that a dose intermediate to the two tested would be required to obtain plasma levels approximating the average level in adults given an equivalent dose.

Altered hepatic blood flow and drug disposition

SummaryFor some drugs, delivery to the liver by the hepatic circulation is an important determinant of removal by this organ. Classical pharmacokinetic analyses cannot predict the changes produced by altering any of the biological determinants of drug elimination by the liver; hepatic blood flow, metabolic enzyme activity, drug binding and route of administration. However, with the use of a physiological model of hepatic drug elimination, such predictions can be made. This model has been tested experimentally and appears to be valid.Hepatic blood flow can vary over about a 4-fold range from half normal flow to twice normal flow. These variations are produced by physiological, pathological or pharmacological changes affecting the circulation. For drug clearance to be affected significantly by these changes in flow, the drug must be avidly removed by the liver as reflected in a high hepatic extraction ratio and intrinsic hepatic clearance. This latter term is a useful way to characterise the ability of the liver to irreversibly remove drug from the circulation in the absence of any flow limitation. The clearance of drugs with low intrinsic clearances will not be affected significantly by changes in liver blood flow.

The Disposition of Propranolol

After propranolol administration into the portal vein of doses less than 0.8 mg/kg, little drug appeared in the systemic circulation and hepatic extraction was greater than 95 %. With increasing dose,

Effects of age and cigarette smoking on propranolol disposition

The effects of age and cigarette smoking on the disposition of propranolol have been investigated in 27 normal men, aged 21 to 73 yr. The drug was administered orally (80 mg) every 8 hr and 40 µCi intravenous 3H‐propranolol were administered simultaneously with the seventh dose. Labeled and unlabeled propranolol concentrations were determined in serial blood samples obtained over the next 8 hr. Subgrouping the oral blood concentration/time data according to age (younger or older than 35 yr) showed that the mean levels in the older group were as much as twofold those in the younger group, and that the terminal half‐life (t½β) was prolonged with age (4.19 ± 1.38 vs. 5.05 ± l.36 hr, mean ± SD; p = 0.03). Substratification of cigarette smokers (>10 cigarettes daily) from nonsmokers indicated that the mean levels in the nonsmokers were 200% higher but there was no t½β difference. Despite the considerable interindividual variability, there was a trend for the weight‐normalized, average steady‐state levels to be lower in smokers than in nonsmokers, with the difference becoming smaller with increasing age. Analysis of the data indicated that the intrinsic total clearance of propranolol decreased with age only in the smokers, and toward the constant value of the nonsmokers, while apparent liver blood flow declined equally with age in both groups. Consequently, systemic‐clearance correlated negatively with age in the smokers and in the group as a whole. No age relationships were found in the volume of distribution and, thus, correlations of age and t½β were of the same order as those of systemic clearance. No changes were observed in systemic availability or plasma binding with aging in either group. It, therefore, appears that cigarette smoking habits are important in the altered steady‐state kinetics of propranolol that develops with aging. The results are consistent with a decreased induction of drug‐metabolizing enzyme with aging.

Proposed Mechanisms of Propranolol's Antihypertensive Effect in Essential Hypertension

We studied the antihypertensive effect of propranolol alone and in combination with diuretics in 13 patients with high, 18 with normal and nine with low-renin essential hypertension whose blood-pressure response to diuretics was previously established. Propranolol (160 mg daily) significantly lowered mean arterial pressure in high-renin (129 +/- 2.6 to 114 +/- 2.1 mm Hg) and normal-renin (131 +/- 2.7 to 119 +/- 3.5 mm Hg) patients but not in low-renin patients. A positive correlation (r = 0.36, P less than 0.05) between fall in pressure and fall in plasma renin activity occurred at this dose when the whole group was considered. An antihypertensive effect occurred in both high-renin and low-renin hypertension during large-dose (320 to 960 mg daily) propranolol therapy. This effect was independent of changes in plasma renin activity. The antihypertensive effects of propranolol and diuretics were additive in normal-renin and high-renin hypertension. These data suggest that propranolols pressure-lowering activity is due to both renin-dependent and renin-independent effects.

Biological determinants of propranolol disposition in man.

Propranolol disposition has been investigated in 15 normal subjects with the use of a protocol which allowed simultaneous determination of the kinetics of the drug after both intravenous and oral administration by giving H3‐propranolol intravenously and native drug orally. In addition, plasma propranolol binding and the bloodlplasma propranolol concentration ratio (B/P) were measured. The data were used to calculate hepatic blood flow as well as systemic drug clearance from the blood and intrinsic clearance, which is an estimate of the activity of the drug‐metabolizing enzymes. Under the steady‐state conditions used, the hepatic extraction ratio was found to be 64% ± 2.5% (mean ± SE) resulting in a bioavailability of 36% ± 2.6%. Calculated liver blood flow varied from 778 to 2,162 ml/min, and, as predicted, the systemic clearance of propranolol (0.61 to 1.52 L/min) was correlated with both liver blood flow and intrinsic drug clearance (1.16 to 5.08 L/min). Variations in plasma drug binding had no effect on systemic clearance. Because of presystemic or “first‐pass” elimination, the variation in both free and total propranolol levels was greater after oral (5‐fold) than intravenous administration (2.5‐fold). We conclude that the approach described allows quantification of all of the biological determinants of propranolol disposition in subjects with normal hepatic vasculature.

Disposition of propranolol V. Drug accumulation and steady‐state concentrations during chronic oral administration in man

In 6 normal volunteers, a twofold accumulation of propranolol in the blood was observed during chronic oral administration of 80 mg every 6 hours that was unpredicted on the basis of the drugs half‐life. No accumulation occurred in 2 subjects given 20 mg intravenously every 6 hours. The observed drug accumulation resulted from two mechanisms. During administration of the first dose an avid hepatic extraction process became saturated after removal of about 30 mg and remained saturated during the dosage interval. This resulted in a 60% increase in the amount of drug reaching the systemic circulation at steady state compared to that after a single dose. It is suggested that the avid hepatic extraction is a result of high‐affinity drug binding and that the increase in availability is due to saturation of this binding site. In addition, the increase in drug availability was sufficient to partially saturate drug metabolism and decrease systemiC drug clearance, resulting in a 44% increase in drug half‐life. These data were supported by the finding that during steady state folloWing 6 hourly oral propranolol administration to 7 subjects, plasma levels were proportional to the dose up to 160 mg per day, suggesting first‐order drug elimination in the presence of a saturated high affinity binding site in the liver. An average of between 160 and 320 mg per day metabolism becomes nonlinear, resulting in a disproportionate increase in plasma concentrations. These studies indicate that saturable hepatic tissue binding, as well as safurable metabolism, can result in nonlinear kinetics of drug disposition.