Unaltered serum propranolol binding by meal‐induced variations in fatty acids.

Naranjo, Claudio A.; Sellers, E. A.; Khouw, V

doi:10.1111/j.1365-2125.1982.tb01425.x

Cited by 5 publications

(4 citation statements)

References 13 publications

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“…Because propranolol seems to be completely absorbed in the fasting state [20], and as increased plasma binding of propranolol is not a likely cause for its increased AUC [21], the current and previous findings support the view that concomitant intake of a protein-rich meal may evoke an increase in propranolol bioavailability that involves reduced presystemic metabolism [1][2][3][4][5]7]. The findings further support the view that a carbohydrate-rich, proteinpoor meal has little or no such effect [2,3,6].…”

Section: Discussionsupporting

confidence: 82%

Mechanisms and variations in the food effect on propranolol bioavailability

Liedholm

Wåhlin-Boll

Melander

1990

Eur J Clin Pharmacol

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Mechanisms and variations in the food-induced increase in the bioavailability of propranolol were assessed by single-dose (80 mg) studies in healthy volunteers who took the drug on an empty stomach, immediately after a protein-rich breakfast, and together with a carbohydrate-rich, protein-poor breakfast. Concomitant intake of the protein-rich, but not the carbohydrate-rich, protein-poor breakfast, increased the bioavailability of propranolol in most, but not all, subjects. The food (protein) effect displayed much inter-individual variation, from a decrease to a 250% increase, which could be explained, at least in part, by a correlation between the oral clearance of propranolol and the food-induced increase in its bioavailability. The food effect was not associated with decreased total availability, but with delayed appearance, of the oxidative metabolites 4-OHP, NLA and PG. Hence the food (protein) effect does not seem to be caused by enzyme inhibition, but rather it is due to reduced hepatic extraction of propranolol, probably consequent to an increase hepatic entry rate. When taken together with the protein-rich breakfast, propranolol usually appeared in systemic blood at least as early as when taken on an empty stomach, implying that gastric absorption of propranolol may be possible in the presence of protein-rich food. Within the individual the food effect was reproducible, but its magnitude showed an intraindividual variation that may reflect its dependence upon the rates of gastrointestinal absorption and splanchnic-hepatic blood flow, and hence upon the rate of hepatic drug entry.

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Section: Discussionsupporting

confidence: 82%

Mechanisms and variations in the food effect on propranolol bioavailability

Liedholm

Wåhlin-Boll

Melander

1990

Eur J Clin Pharmacol

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“…It is quite clear that food-induced changes in blood flow have little effect on the first-pass metabolism of highly extracted drugs. It has also been shown that protein binding of basic drugs, such as lidocaine and propranolol, is unaffected by concomitant food intake (Bai et al 1983;Elvin et al 1981;Feely et al 1983;Naranjo et al 1982).…”

Section: Food Effectsmentioning

confidence: 96%

Individual Variation in First-Pass Metabolism

Tam

1993

Clinical Pharmacokinetics

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Individual variation in pharmacokinetics has long been recognised. This variability is extremely pronounced in drugs that undergo extensive first-pass metabolism. Drug concentrations obtained from individuals given the same dose could range several-fold, even in young healthy volunteers. In addition to the liver, which is the major organ for drug and xenobiotic metabolism, the gut and the lung can contribute significantly to variability in first-pass metabolism. Unfortunately, the contributions of the latter 2 organs are difficult to quantify because conventional in vivo methods for quantifying first-pass metabolism are not sufficiently specific. Drugs that are mainly eliminated by phase II metabolism (e.g. estrogens and progestogens, morphine, etc.) undergo significant first-pass gut metabolism. This is because the gut is rich in conjugating enzymes. The role of the lung in first-pass metabolism is not clear, although it is quite avid in binding basic drugs such as lidocaine (lignocaine), propranolol, etc. Factors such as age, gender, disease states, enzyme induction and inhibition, genetic polymorphism and food effects have been implicated in causing variability in pharmacokinetics of drugs that undergo extensive first-pass metabolism. Of various factors considered, age and gender make the least evident contributions, whereas genetic polymorphism, enzymatic changes due to induction or inhibition, and the effects of food are major contributors to the variability in first-pass metabolism. These factors can easily cause several-fold variations. Polymorphic disposition of imipramine and propafenone, an increase in verapamil first-pass metabolism by rifampicin (rifampin), and the effects of food on propranolol, metoprolol and propafenone, are typical examples. Unfortunately, the contributions of these factors towards variability are unpredictable and tend to be drug-dependent. A change in steady-state clearance of a drug can sometimes be exacerbated when first-pass metabolism and systemic clearance of a drug are simultaneously altered. Therefore, an understanding of the source of variability is the key to the optimisation of therapy.

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“…Propranolol blood and tissue binding has been studied in great detail [7,30-32]. The propranolol tissue distribution seems to be determined primarily by the phosphatidylserine composition of the tissue [33].…”

Section: Resultsmentioning

confidence: 99%

“…[5] found an average meal induced increase in total liver blood flow of about 34% using indocyanine green [5]. It has also been shown that the serum propranolol binding is not affected by meal induced variations in fatty acids [30] so that the model parameters related to lipid binding (freepl and ktiss[i]) were not allowed to vary between the fasting and standard meal experiments.…”

Section: Resultsmentioning

confidence: 99%