The effect of propranolol on catecholamine clearance

Normal subjects given propranolol increased their plasma t1/2 for infused isoproterenol from 2.68 to 6.25 minutes. Propranolol increased plasma norepinephrine (NE) levels only slightly. Propranolol increased the t1/2 of isoproterenol but not that of NE in men with autonomic nervous system degeneration. This suggests that propranolol acts on nonneuronal uptake-2 processes, rather than on uptake-1 mechanisms. alpha-Blockers slow uptake-1 and beta-blockers slow uptake-2 processes. When 27 subjects exercised, those who attained the highest plasma levels of the alpha- and beta-receptor agonist NE also had the briefest apparent t1/2 for NE. Adrenergic receptor blocking drugs slow catecholamine clearance. NE may stimulate its own clearance.     

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.     

Cigarette smoking and theophylline metabolism: effects of cimetidine

The inhibition of theophylline metabolism by cimetidine was investigated in young male cigarette smokers (greater than 20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) over days 1 to 7 or 8 to 14. On days 7 and 14, a tracer dose (10 mg) of stable isotope-labeled theophylline was injected intravenously with the oral dose of theophylline. Serial plasma samples were then obtained for 24 hours and both molecular forms of theophylline were assayed by mass spectrometry after purification by HPLC. Theophylline bioavailability, volume of distribution, and protein binding were of the same order in both groups and were not affected by cimetidine. Although the basal theophylline elimination rate constant was 46% greater and clearance was 54% greater in smokers than in nonsmokers, the proportionate changes in steady-state plasma concentrations, t1/2, and clearance due to cimetidine were much the same in both groups. Plasma thiocyanate concentrations were higher in smokers than in nonsmokers and were related to theophylline clearance. Our findings indicate that cimetidine inhibits theophylline metabolism to a similar extent in both smokers and nonsmokers. Determination of plasma thiocyanate levels may be valuable in the prediction of theophylline clearance.     

Cigarette smoking and theophylline metabolism: effects of phenytoin

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 +/- 2.0 micrograms/ml) and smokers (11.5 +/- 0.9 micrograms/ml). Control theophylline elimination half-life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half-life (26.8% +/- 5.6% in smokers and 25.8% +/- 3.5% in nonsmokers) and clearance (48.0% +/- 10.1% in smokers and 39.7% +/- 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.     

Effect of smoking on caffeine clearance

The elimination of caffeine from saliva was compared in groups of healthy smokers (n = 13) and nonsmokers (n = 13). Mean caffeine t1/2 in smokers (3.5 hr) was shorter than that in the nonsmokers (6.0 hr). The body clearance of caffeine in the smokers (155 +/- 16 ml . kg-1 . hr-1) was greater than that in the nonsmokers (94 +/- 18 ml . kg-1 . hr-1) (p less than 0.05). No significant difference was noted in the apparent volume of distribution in smokers (720 +/- 67 ml . kg-1) and nonsmokers (610 +/- 80 ml . kg-1). These differences probably reflect the induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity in smokers. The increased clearance of caffeine by smokers may contribute to the higher consumption of coffee reported to occur in this group.     

Effects of passive smoking on theophylline clearance

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.     

Adverse effects of smoking in the renal patient

Smoking is a known risk factor for cardiovascular diseases, cancer, and several other health problems. It is the number one preventable cause of death in modern countries. The first evidence that smoking may be a renal risk factor was published in 1978. Since then, several studies documented that smoking is nephrotoxic in patients with diabetic and non-diabetic renal disease. Data from the Multiple Risk Factor Intervention Trial indicate that smoking even increases the renal risk in the general male population: an increased relative risk for end-stage renal failure (ESRF) was found for smokers as compared to non-smokers (up to 1.69 for heavy smokers). Several potential mechanisms of smoking-induced renal damage have been discussed, e.g. increase in blood pressure, alteration of intrarenal hemodynamics, as well as activation of the sympathetic nerve, the reninangiotensin and the endothelin systems. The pathomechanisms are, however, only partly understood. Once ESRF has become established, the failure to discontinue smoking adversely affects the prognosis of patients on renal replacement therapy, mainly by increasing the risk of cardiovascular complications. Discontinuation of smoking has been shown to improve both renal and cardiovascular prognosis in the renal patient and is probably the single most effective measure to retard progression of renal failure.     

Assessment of renal function by inulin clearance: comparison with creatinine clearance as determined by enzymatic methods

We compared creatinine clearances determined by enzymatic (Kodak Ektachem 700 single-slide, Boehringer Mannheim creatinine PAP) and nonenzymatic (Jaffé, HPLC) methods with glomerular filtration rate measured by inulin clearance in patients with varying degrees of renal function. The Kodak enzymatic assay gave values for creatinine 2 to 3 mg/L higher than the other methods. This resulted in significantly lower creatinine clearances than inulin clearances and creatinine clearances determined by the other methods. However, correlations between all methods for serum and urinary creatinine values and clearances were good. To avoid between assay (enzymatic vs nonenzymatic) discrepancies, manufacturers should agree to an acceptable standard of calibration under the usual conditions used with patients.     

Increased clearance of propranolol and theophylline by high-protein compared with high-carbohydrate diet

The objective of this study was to determine whether changes in dietary protein and carbohydrate influence the oral clearance of propranolol, a high-clearance drug, and theophylline, a low-clearance drug. Six normal subjects studied in a clinical research center each received a single oral dose of propranolol, 80 mg, and theophylline, 5 mg/kg, after having been on each of two well-defined diets for a period of 10 days. When the diet was altered from high carbohydrate/low protein to low carbohydrate/high protein, the oral clearance of propranolol increased by 74% +/- 20% (mean +/- SE; range 9% to 156%; P less than 0.01) with no change in plasma half-life or plasma binding. This dietary change resulted in an increase in theophylline clearance of 32% +/- 6% (range 18% to 50%; P less than 0.02) and a corresponding decrease in plasma half-life of 26% +/- 6% (range 6% to 42%; P less than 0.05) with no alteration in the apparent volume of distribution. These observations reemphasize the importance of diet in drug disposition and suggest that the clearance of high-clearance drugs like propranolol is more susceptible than the clearance of low-clearance drugs to dietary manipulations, effects that may have to be considered in drug therapy.     

Determinants of the rate of nicotine metabolism and effects on smoking behavior

BACKGROUND: Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. METHODS: We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. RESULTS: The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04). CONCLUSION: In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.     

Reduced hepatic clearance of propranolol induced by chronic carbon tetrachloride treatment in rats

Effect of liver injury induced by chronic treatment with carbon tetrachloride for 1 to 4 months on hepatic clearance of propranolol was investigated in male Wistar rats. Plasma propranolol level after i.v. and p.o. dosing (1.0 mg/kg) was always higher in the rats which were treated for 2 and 4 months than in control (sham-injected) rats. The chronic treatment reduced hepatic clearance of propranolol significantly, yielding only approximately 30 to 50% of the control clearance value. Distribution volume of this drug was also significantly reduced by the chronic treatment but seemed to be less sensitive to the treatment than the hepatic clearance. Accordingly, the elimination rate constant was decreased slightly in the rats treated longer than 2 months. The chronic treatment for 2 and 4 months also reduced intrinsic hepatic clearance substantially. The hepatic clearance estimated for both these control and chronically treated rats was significantly dependent on the liver blood flow. Furthermore, propranolol was eliminated much more slowly in the injured liver of the rat which was treated for 2 or 4 months than in the control liver when perfused in in vitro technique. It is, therefore, suggested that the metabolic dysfunction induced by chronic treatment with carbon tetrachloride may be directly related to substantial changes in anatomical arrangement of the hepatic circulation (portasystemic shunting), which may be due to a fibrosis of the tissue.     

Biologic effects of parathyroid hormone metabolites: implications for renal bone disease.

PTH fragments consisting of the C-terminal portion of the molecule may have biologic effects and may modify the actions of PTH. Evidence for the presence of a C-terminal PTH receptor further supports a biologic role for such fragments. Because C-PTH fragments accumulate in patients with renal insufficiency, it is possible that they may contribute to renal bone disease. The precise role of circulating C-PTH fragments in the pathogenesis, diagnosis, and management of renal osteodystrophy, however, remains to be determined. Future studies of the biologic effects and regulation of these fragments may lead to better understanding of skeletal biology and may also improve our approach to the diagnosis and treatment of renal bone disease.     

Comparison between short-term renal haemodynamic effects of propranolol and nadolol in essential hypertension: a cross-over study

The effect of 4-6 weeks' treatment with propranolol and nadolol on effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) was studied, in 14 patients with essential hypertension, in single blind, random and cross-over design. Both drugs caused comparable effective lowering of pulse and blood pressure. When taken as the first drug, propranolol caused significant reduction in ERPF and GFR and a rise in filtration fraction (FF) and renal vascular resistance (RVR), whereas nadolol caused distinct rise in ERPF and a fall in FF and RVR but GFR remained unchanged. These haemodynamic effects were reduced when propranolol was given immediately after the withdrawal of nadolol and were obviated when nadolol followed propranolol therapy. This suggested a carry-over effect of the first drug into the second phase of treatment. We conclude that with short term therapy in essential hypertension, propranolol has a renal vasoconstrictor and nadolol a vasodilator effect.     

Influence of debrisoquin phenotype on the inducibility of propranolol metabolism

The effects of rifampin (600 mg) once daily for 22 days on the total and fractional metabolic clearances of propranolol were determined in a group of six genetically extensive (EM) and six poor metabolizers (PM) of debrisoquin. The impaired ability of PMs to metabolize propranolol to the ring-oxidized metabolite 4-hydroxypropranolol was confirmed. The total oral clearance of propranolol increased about fourfold in both phenotypes from 219.2 +/- 52.8 to 976.7 L/hr in the EMs and from 75.0 +/- 12.6 to 289.8 +/- 78.2 L/hr in the PMs. The extent of induction of glucuronidation was similar in the two groups. 4-Hydroxylation was induced in both phenotypes but the increase was fifteenfold greater in EMs than in PMs. This would imply that the cytochrome P-450 determined by the debrisoquin allele or some coinherited 4-hydroxylase(s) was induced to a greater extent in EMs than PMs.