Pharmacokinetics of bambuterol during oral administration to asthmatic children

Ahlström, H; Alvero, Josefino R.; Alvero, Rita Grace; Espos, Roberto A.; Fajutrao, Liberty; Herrera, Jocelyn; Kjellman, Bengt; Kubista, Josef; Leviste, Carolina; Meyer, Peter; Oldæus, Göran; Siricururat, Areerat; Vichyanond, Pakit; Wettrell, Göran; Wong, Ellick; Laxmyr, Lena; Nyberg, Lars; Olsson, Håkan; Weibull, Eva; Rosenborg, Johan

doi:10.1046/j.1365-2125.1999.00028.x

Cited by 12 publications

(7 citation statements)

References 11 publications

(7 reference statements)

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“…This might be due to the existence of two BChE variants having different inhibition rates and not contributing equally to the measured activity. 17 It is theoretically possible that the deviation is the result of decarbamoylation of the catalytic serine, but this seems unlikely since it is known that usual and atypical variants decarbamoylate spontaneously at similar and very slow rates, of about 0.003 min 21 . 18 Re-inhibition of free BChE by the monocarbamate produced after the first step of bambuterol hydrolysis is also improbable due to a great excess of nonhydrolysed bambuterol.…”

Section: Resultsmentioning

confidence: 99%

Interaction of Human Butyrylcholinesterase Variants with Bambuterol and Terbutaline

Kovarik

Simeon-Rudolf

2004

Journal of Enzyme Inhibition and Medicinal Chemistry

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Bambuterol, a dimethylcarbamate, carbamoylates butyrylcholinesterase (BChE; EC 3.1.1.8). The carbamoylated enzyme is not very stable and the final product of the two-step hydrolysis is a bronchodilator drug, terbutaline (1-(3,5-dihydroxyphenyl)-2-t-butylamino-ethanol sulphate). Both bambuterol and terbutaline inhibit BChE, but their affinities differ in human serum BChE variants (U, A, F, K and S) due to their positive charge. Bambuterol inhibition rate constants for the homozygous usual (UU), Kalow (KK), fluoride-resistant (FF) or atypical (AA) variant ranged from 4.4 to 0.085min (-1)microM(-1). Terbutaline showed competitive reversible inhibition for all BChE variants. The dissociation constants for UU, FF and AA homozygotes were 0.18, 0.31 and 3.3 mM, respectively. The inhibition rate or dissociation constants for heterozygotes were distributed between the respective constants for the corresponding homozygotes. A 50-fold difference in inhibition between the UU and AA enzyme might affect terbutaline release in humans. The affinity of all studied BChE variants for terbutaline was low, which suggests that terbutaline originating from bambuterol hydrolysis should not affect the hydrolysis of bambuterol by BChE.

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Section: Resultsmentioning

confidence: 99%

Interaction of Human Butyrylcholinesterase Variants with Bambuterol and Terbutaline

Kovarik

Simeon-Rudolf

2004

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…(where e is a mathematical constant with the approximate value 2.7183), is particularly appropriate for modeling the pharmacokinetics of oral drugs [20][21][22][23][24]. Initial values for a, b, c, x 0 , and y 0 (which determine the shape of the curve) were selected on the basis of the range of values in the data set, according to SigmaPlot default parameters.…”

Section: Recruitment Initial Evaluation and Treatmentmentioning

confidence: 99%

Whole Blood Bactericidal Activity during Treatment of Pulmonary Tuberculosis

Wallis¹,

Vinhas

Johnson

et al. 2003

J INFECT DIS

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The timely evaluation of new drugs that can be used to shorten tuberculosis (TB) treatment will require surrogate markers for relapse. This study examined bactericidal activity against intracellular Mycobacterium tuberculosis in whole blood culture (whole blood bactericidal activity; WBA) during TB treatment. In the absence of chemotherapy, immune mechanisms in patient blood resulted in bacteriostasis, whereas administration of oral chemotherapy resulted in bacillary killing. Total WBA per dose was greater during the intensive phase of treatment than during the continuation phase (mean, -2.32 vs. -1.67 log(10) cfu-days, respectively; P<.001). Cumulative WBA throughout treatment was greater in subjects whose sputum cultures converted to negative by the eighth week of treatment than in those for whom conversion was delayed (mean, -365 vs. -250 log(10) cfu-days; P=.04) and correlated with the rate of decrease of sputum colony-forming unit counts during the first 4 weeks of treatment (P=.018), both of which are indicative of prognosis. These findings indicate that measurement of WBA may have a role in assessing the sterilizing activity of new anti-TB drugs.

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“…7) showed that the increase of production rate expected upon the increase of substrate concentration is almost perfectly balanced by the decrease of rate due to the reduction of active enzyme. This is especially noticeable in the range of BMB concentrations responsible for a maximum inhibition within 50% and 80%, which is the normal range of inhibition measured upon oral administration of rac-BMB in pharmacokinetic studies (Sitar et al, 1992;Nyberg et al, 1998;Ahlström et al, 1999). Thus, the inhibition of the enzyme affects the initial production rate of TBT by keeping it constant over a relatively wide range of concentrations of administered BMB, rather than lowering it (Fig.…”

Section: Discussionmentioning

confidence: 97%

Stereoselective Inhibition of Human Butyrylcholinesterase by the Enantiomers of Bambuterol and Their Intermediates

Pistolozzi

Hong

et al. 2014

Drug Metab Dispos

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This work describes the sequential hydrolysis of bambuterol enantiomers and their monocarbamate metabolites (MONO) catalyzed by human butyrylcholinesterase (BChE) as well as the enzyme inhibition resulting from this process. Particular emphasis is given to the contribution given by MONO to the enzyme inhibition because it was not fully characterized in previous works. Bambuterol and MONO enantiomers displayed the same time-and concentrationdependent mechanism of interaction with the enzyme. The hydrolysis kinetics of both bambuterol and MONO was enantioselective, and the (R)-enantiomer of each compound was hydrolyzed fourfold faster than the respective (S)-enantiomer. Even though the enzyme inhibition rates of (R)-and (S)-MONO were much slower than those of their respective bambuterol enantiomers (∼15-fold), both MONO enantiomers showed a significant BChE inhibition when physiologically relevant concentrations of enzyme and inhibitors were used (∼50% of their respective bambuterol enantiomers). The kinetic constants obtained by testing each single compound were used to model the contribution given by MONO to the enzyme inhibition observed for bambuterol. The hydrolysis of MONO enantiomers enhanced the inhibitory power of bambuterol enantiomers of about 27.5% (R) and 12.5% (S) and extended more than 1 hour the duration of inhibition. The data indicate that MONO contribute significantly to the inhibition of BChE occurring in humans upon administration of normal doses of bambuterol. In addition, the hydrolysis of MONO resulted in the rate-limiting step in the conversion of bambuterol in its pharmacologically active metabolite terbutaline; therefore, MONO concentrations should always be monitored during pharmacokinetic studies of bambuterol.

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Pharmacokinetics of bambuterol during oral administration to asthmatic children

Cited by 12 publications

References 11 publications

Interaction of Human Butyrylcholinesterase Variants with Bambuterol and Terbutaline

Interaction of Human Butyrylcholinesterase Variants with Bambuterol and Terbutaline

Whole Blood Bactericidal Activity during Treatment of Pulmonary Tuberculosis

Stereoselective Inhibition of Human Butyrylcholinesterase by the Enantiomers of Bambuterol and Their Intermediates

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