Pharmacokinetics and metabolism of indapamide: A review

Campbell, David B.; Taylor, A. R.; Hopkins, Y. W; Jl, Williams

doi:10.1185/03007997709110219

Cited by 73 publications

(28 citation statements)

References 10 publications

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“…Incremental AUCs and maximum reductions in blood glucose were correlated with plasma BTS 67 582 AUCs and peak concentrations, respectively. This is in keeping with the effect of sulphonylureas [16] where, for example, correlations between the fall in glucose levels and drug concentrations were observed during the first 4 h after dosage of gliclazide in healthy volunteers [17]. Although BTS 67 582 has been seen to exert a hyperinsulinaemic effect in animal studies (Marita & Kaul, unpublished), no correlation between plasma insulin and plasma BTS 67 582 was observed in this study.…”

Section: Discussionsupporting

confidence: 88%

Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.

Byrom

Rotherham

Bratty

1994

Brit J Clinical Pharma

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1 The relationships between blood glucose, plasma insulin and plasma BTS 67 582 concentrations were studied in a randomised, placebo-controlled, four-way crossover study involving 16 healthy male volunteers aged between 19 and 43 years. Single oral doses of 125, 250 and 500 mg BTS 67 582 were studied. 2 Fasting blood samples were taken pre-dose and half-hourly for 8 h post-dose. Mean peak plasma concentrations of BTS 67 582 were 518, 1076 and 2435 ng ml-1 for doses of 125, 250 and 500 mg, respectively. Mean maximum reductions in blood glucose were 1.13, 1.59 and 1.78 mmol 1-1, and mean maximum increases in plasma insulin were 26, 14 and 21 pu ml-' for the three doses, respectively. Changes in incremental area under the curve (AUC) of blood glucose were correlated with changes in plasma BTS 67 582 AUC. The maximum reduction in blood glucose was correlated with the peak plasma BTS 67 582 concentration. No correlations between plasma insulin and plasma BTS 67 582 concentrations were observed. 3 Anticlockwise hysteresis was evident in concentration-effect curves, but less evident following subtraction of placebo data, and was mainly due to an underlying downward trend in fasted blood glucose levels with time evident under placebo treatment. This suggests that hypoglycaemic effects were related to systemic BTS 67 582 concentrations, suggesting that active metabolites of the drug do not make a major contribution to acute hypoglycaemic effects. 4 A log-linear model described the relationship between blood glucose and plasma BTS 67 582 concentrations for 14 of the 16 volunteers. Log-linear and Emax models described this relationship when the data were pooled. 5 A single compartment pharmacokinetic model with no lag time was fitted to the plasma concentration data of BTS 67 582. The pharmacokinetics of the drug were generally linear over the three doses studied. 6 Concentration-effect and pharmacokinetic models were combined to produce a predictive model of the reduction in blood glucose with time following doses of BTS 67 582. A potential application of this model is for the prediction of reductions in glycosylated haemoglobin under longterm administration of BTS 67 582, using reported correlations with blood glucose.

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Section: Discussionsupporting

confidence: 88%

Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.

Byrom

Rotherham

Bratty

1994

Brit J Clinical Pharma

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“…This may suggest that slow accumulation in the target organ takes place, especially since the thiazide-like agent indapamide was found at a 9-fold higher concentration in vascular smooth muscle cells than in the plasma. 40 Consequently, despite the high concentrations used in this study, it is conceivable that the mechanism described may be relevant to the actions of these agents in vivo after long-term administration.…”

Section: Direct Vasoactivity Of Carbonic Anhydrase Inhibitorsmentioning

confidence: 88%

Inhibition of Carbonic Anhydrase Accounts for the Direct Vascular Effects of Hydrochlorothiazide

et al. 1999

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Abstract-Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (K Ca ) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because K Ca channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pH i ) were measured simultaneously with 2Ј,7Ј-bis(2-carboxyethyl)-5(6)Ј-carboxyfluorescein (BCECF-AM). Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16Ϯ8% relaxation) compared with hydrochlorothiazide (74Ϯ12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of K Ca channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Key Words: hydrochlorothiazide Ⅲ carbonic anhydrase inhibition Ⅲ muscle, smooth, vascular Ⅲ pH i Ⅲ potassium channels T hiazide diuretics were developed in the 1950s by chemical modification of carbonic anhydrase inhibitors. Although their blood pressure-lowering effects have been well documented, their mechanism of action is still not fully resolved. The principal site of action of thiazides is the early segment of the distal nephron, where they inhibit a luminal transmembrane-coupled NaCl transport system. In the long term, thiazides act by reducing peripheral resistance rather than by their diuretic effects, 1 and therefore a direct vascular effect has been proposed.Previous studies in isolated human and guinea pig resistance arteries have established a direct vasodilator activity of hydrochlorothiazide. This vasorelaxant response to hydrochlorothiazide was abolished by charybdotoxin and iberiotoxin, both selective blockers of large-conductance Ca 2ϩ -activated potassium (K Ca ) channels, but not by inhibitors of other vascular K ϩ channels. 2 On the basis of the fact that thiazide-like drugs such as cicletanine and diazoxide lead to hyperpolarization in vascular smooth muscle cells 3 and the fact that hydrochlorothiazide increases 86 Rb efflux as a marker of K ϩ efflux, 2,4 it was proposed that hydrochlorothiazide opens K Ca channels, thereby leading to K ϩ efflux and membrane hyperpolarization. The resultant closure of voltage-dependent Ca 2ϩ channels leads to a fall in [Ca 2ϩ ] i and vasorelaxation. 5 In addition to [Ca 2ϩ ] i , the open state probability of the K Ca channel is also modulated by intracellular pH (pH i ). Channel opening is inhibited by intracellular acidosis in carotid body cells, 6 while in isolated blood vessels intracellular alkalinization leads to relaxation asso...

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“…The knowledge of origin and assumed structure of fragment ions provides important information about the administered drug and its modifications, which is essential for different analytical laboratories, e.g., for those performing anti-doping, clinical, or forensic analyses. Modifications of drugs such as diuretics can be caused by metabolism [2][3][4][5][6] or by intentional alterations of the molecules prior to administration in order to characterize the influence of functional groups on the efficiency of the particular remedy [7][8][9][10]. For instance, the diuretic effect of chlorothiazide (6-chloro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) was increased by a factor of 10 by the hydration of its N-3¢C-4 double bond to hydrochlorothiazide (6-chloro-7-sulfamoyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide) [11][12][13], and the substitution of a 2,6-dimethylanilide residue by a 2,6-dimethylpiperidyl group and a hydroxyl group by a hydrogen changes the diuretic agent xipamide to clopamide ( Figure 1).…”

mentioning

confidence: 99%

Effect of the location of hydrogen abstraction on the fragmentation of diuretics in negative electrospray ionization mass spectrometry

Thevis

Schänzer

Schmickler

2003

J. Am. Soc. Mass Spectrom.

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The diuretic agents bumetanide, xipamide, indapamide, and related compounds were investigated in order to determine the effect of different ionization sites on their collisionally activated dissociation and the corresponding fragmentation pathways. Therefore, analytes were selectively alkylated, and structural analogues as well as deuterium labeled compounds synthesized, which contain a reduced number of ionizable hydrogen atoms. Thus, specific hydrogen abstractions and their correlated dissociation routes of the negatively charged molecules were eliminated, providing evidence for the influence of the location of ionization on product ion spectra. Fragment ions such as m/z 78 indicate ionization at the commonly present sulfamoyl residue of diuretics but does not exclude additional ionization sites. Product ion spectra of the investigated diuretic agents proved to be composed by fragmentations initiated from different hydrogen abstractions. Moreover, the generation of radical anions by collision-activated dissociation of even-electron precursor ions was observed, the generation of which is discussed by proposed fragmentation pathways. (J Am Soc Mass Spectrom 2003, 14, 658 -670)

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Pharmacokinetics and metabolism of indapamide: A review

Cited by 73 publications

References 10 publications

Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.

Relationship between hypoglycaemic response and plasma concentrations of BTS 67 582 in healthy volunteers.

Inhibition of Carbonic Anhydrase Accounts for the Direct Vascular Effects of Hydrochlorothiazide

Effect of the location of hydrogen abstraction on the fragmentation of diuretics in negative electrospray ionization mass spectrometry

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