Determination of propranolol and six metabolites in human urine by high-pressure liquid chromatography

Pritchard, J. Frederick; Schneck, Dennis W.; Hayes, Arthur H.

doi:10.1016/s0378-4347(00)82062-9

Cited by 60 publications

(18 citation statements)

References 12 publications

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“…Unfortunately, poor stability in solution made the matrix effect or recovery assessment for 4-hydroxypropranolol impossible. This has been reported previously (Pritchard et al., 1979) and samples required additives (sodium metabisulfite and sodium bisulfite) to maintain stability. Overall, matrix effects were relatively minor for most biotransformation products ranging from 4% suppression to 9% enhancement.…”

Section: Resultssupporting

confidence: 90%

Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry

et al. 2017

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Methods were developed to assess uptake and elimination kinetics in Gammarus pulex of nine pharmaceuticals (sulfamethazine, carbamazepine, diazepam, temazepam, trimethoprim, warfarin, metoprolol, nifedipine and propranolol) using targeted LC-MS/MS to determine bioconcentration factors (BCFs) using a 96 h toxicokinetic exposure and depuration period. The derived BCFs for these pharmaceuticals did not trigger any regulatory thresholds and ranged from 0 to 73 L kg−1 (sulfamethazine showed no bioconcentration). Metabolism of chemicals can affect accurate BCF determination through parameterisation of the kinetic models. The added selectivity of LC-MS/MS allowed us to develop confirmatory methods to monitor the biotransformation of propranolol, carbamazepine and diazepam in G. pulex. Varying concentrations of the biotransformed products; 4-hydroxypropranolol sulphate, carbamazepine-10,11-epoxide, nordiazepam, oxazepam and temazepam were measured following exposure of the precursor compounds. For diazepam, the biotransformation product nordiazepam was present at higher concentrations than the parent compound at 94 ng g−1 dw. Overall, the results indicate that pharmaceutical accumulation is low in these freshwater amphipods, which can potentially be explained by the rapid biotransformation and excretion.

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Section: Resultssupporting

confidence: 90%

Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry

et al. 2017

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“…Most assays for 4HP in biological fluids involve solvent extraction from an alkalinized sample (Koshakji & Wood, 1987;Kwong & Shen, 1987;Pritchard et al, 1979). However, 4HP is unstable at high pH.…”

Section: Propranolol Metabolite Assaymentioning

confidence: 99%

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Otton

Lennard

et al. 1990

Brit J Clinical Pharma

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1 Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4-hydroxylase (cytochrome P-4501ID6) and the remaining seven were from extensive metaboliser (EM) phenotypes. 2 In the presence of NADPH and oxygen 4-and 5-hydroxylation of propranolol occurred in microsomes from all nine livers, as did propranolol N-desisopropylation. R(+)-propranolol was oxidized preferentially along the three pathways, although enantioselectivity observed for N-desisopropylation may have arisen not only from stereoselectivity in formation rates, but also from stereoselectivity in subsequent microsomal metabolism, possibly by monoamine oxidase. The involvement of monoamine oxidase in the further microsomal metabolism of N-desisopropylpropranolol was indicated by inhibition of the metabolism of this compound when incubated with phenelzine. 3 Cumene hydroperoxide has been proposed to support only the activity of cytochrome P450IID6. This is consistent with the observations that a) propranolol 4-and 5-hydroxylation occurred in microsomes from the EM livers only and b) side-chain oxidation was not observed under these conditions in either PM or EM livers. 4 Using cumene hydroperoxide to support the reactions, the 4-hydroxylation of propranolol showed little enantioselectivity, whereas S(-)-propranolol was 5-hydroxylated about twice as fast as the R(+)-enantiomer. There were highly significant correlations between the rates of 4-and 5-hydroxylation of R(+)-propranolol (r = 0.96, P < 0.001, n = 7 livers) and of S(-)-propranolol (r = 0.98, P < 0.001). Both oxidations were described by single-site Michaelis-Menten kinetics. 5 The findings suggest that P4501ID6 is involved in both the 4-and 5-hydroxylations of propranolol, but that these metabolites can also be formed by other P450 isoenzymes. It is confirmed that P450IID6 does not contribute to the N-desisopropylation of propranolol. Furthermore, the finding that mephenytoin did not inhibit the appearance of this metabolite is not consistent with the results of in vivo studies suggesting the involvement of the same enzyme in the side-chain oxidation of propranolol and the 4-hydroxylation of mephenytoin.

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“…The serum concentrations of propranolol and its three oxidative metabolites 4-hydroxyproprano!ol (4-OHP), propranolol glycol (PG) and naphthoxylactic acid (NLA) were determined by HPLC [19], with minor modifications including a mobile phase of 58% methanol, 41% H20 and 1% glacial acetic acid with one bottle PIC B-7 (Waters Associates) added to each litre (propranolol, 4-OHP and PG), or of 60% methanol and 40% 0.01 M KH2PO4, final pH 3.1 (NLA). Procainamide was used as internal standard for propranolol, 4-OHP and PG, and 2-naphth0xyacetic acid for NLA.…”

Section: Assays Of Propranolol 4-hydroxypropranolol Propranolol Glymentioning

confidence: 99%

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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Determination of propranolol and six metabolites in human urine by high-pressure liquid chromatography

Cited by 60 publications

References 12 publications

Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry

Uptake, biotransformation and elimination of selected pharmaceuticals in a freshwater invertebrate measured using liquid chromatography tandem mass spectrometry

Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.

Mechanisms and variations in the food effect on propranolol bioavailability

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