Pharmacokinetics of the thiazide diuretics

Welling, Peter G.

doi:10.1002/bdd.2510070602

Cited by 56 publications

(34 citation statements)

References 107 publications

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“…In humans, the renal clearance of hydro chlorothiazide is high (approximately 300 ml/ min) and involves glomerular filtration and proximal tubular secretion, whereas rcabsorption was not found [ 11 ]. In our IPK.…”

Section: Discussionmentioning

confidence: 76%

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Saturable Accumulation and Diuretic Activity of Hydrochlorothiazide in the Isolated Perfused Rat Kidney

Masereeuw¹,

Moons²,

Rüssel³

1997

Pharmacology

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The role of tubular accumulation in renal disposition and diuretic efficacy of hydrochlorothiazide was studied in the isolated perfused rat kidney. Hydrochlorothiazide resulted in a dose-dependent increase in the fractional excretion of sodium, chloride and potassium, and in urinary flow and pH. Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion. Hydrochlorothiazide was subject to saturable tubular secretion, following Michaelis-Menten kinetics. Parameters obtained after nonlinear regression analysis were a maximum tubular transport velocity of 42 ± 6 µg/min, a Michaelis-Menten constant of secretion of 38 ± 11 µg/ml and a fraction of excreted drug reabsorbed passively of 0.49 ± 0.03. The thiazide diuretic accumulated extensively in kidney tissue due to active cellular uptake (maximum capacity of renal accumulation of 500 ± 270 µg/g; affinity constant of renal accumulation of 28 ± 16 µg/ml) and passive diffusion. Plots were constructed of the sodium excretion rate versus hydrochlorothiazide perfusate concentration or the renal excretion rate. The perfusate plot could be described by the sigmoid E_max model, while a simplification of the model had to be used for the response curve in urine because a maximum effect was not observed. The apparent maximum effect resulting from the perfusate concentration-response curve and the discrepancy with the renal excretion rate-response curve indicates that the diuretic effect of hydrochlorothiazide is restricted by saturable accumulation and secretion.

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Section: Discussionmentioning

confidence: 76%

“…Ap proximately 40% of the drug is bound to plas ma proteins [11]. Although the mechanism of action of hydrochlorothiazide is still not com pletely elucidated, it is well established that the primary mode of action is inhibition of the sodium chloride cotransport mechanism at the luminal membrane of distal convoluted tubular cells.…”

Section: ]mentioning

confidence: 99%

Saturable Accumulation and Diuretic Activity of Hydrochlorothiazide in the Isolated Perfused Rat Kidney

Masereeuw¹,

Moons²,

Rüssel³

1997

Pharmacology

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“…congestive heart failure) [15]. Based on cumulative urinary excretion studies, the oral bioavailability of hydrochlorothiazide is approximately 70% [15]. Hydrochlorothiazide is excreted almost entirely as unchanged drug in the urine [15].…”

Section: Discussionmentioning

confidence: 99%

“…Absorption of hydrochlorothiazide is generally assumed to obey first order kinetics [15,16], but a zero order process may better characterize the absorption of hydrochlorothiazide from ingested tablets [17]. A number of factors that alter hydrochlorothiazide absorption have been identified, including drugs (e.g.…”

Section: Discussionmentioning

confidence: 99%

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Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

Weir¹,

Dimmitt²,

Lanman

et al. 1998

Biopharm. Drug Dispos.

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Population‐based meta‐analysis of hydrochlorothiazide pharmacokinetics

Wart

Shoaf

Mallikaarjun

et al. 2013

Biopharm & Drug Disp

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Hydrochlorothiazide (HCTZ) is a thiazide diuretic used for the treatment of hypertension and edema associated with fluid overload conditions such as congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM® was used to develop a PK model to characterize the time-course of HCTZ concentrations in plasma and excretion into the urine for healthy subjects and CHF patients. Data from healthy subjects receiving 100 mg of oral HCTZ were supplemented with additional plasma concentration and urinary excretion versus time data published in the literature following administration of oral HCTZ doses ranging from 10 to 500 mg to healthy subjects or patients with renal failure, CHF or hypertension. A two-compartment model with first-order oral absorption, using a Weibull function, and first-order elimination best described HCTZ PK. Creatinine clearance (CLCR ) was a statistically significant predictor of renal clearance (CLR ). Non-renal clearance was estimated to be 2.44 l/h, CLR was 18.3 l/h and T1/2,α was 1.6 h and T1/2,β was 14.8 h for a typical individual with normal renal function (CLCR = 120 ml/min). However, CLR was reduced to 10.5, 5.47 and 2.70 l/h in mild (CLCR = 80 ml/min), moderate (CLCR = 50 ml/min) and severe (CLCR = 30 ml/min) renal impairment, respectively. Model diagnostics helped to demonstrate that the population PK model reasonably predicts the rate of urinary HCTZ excretion over time using dosing history and estimated CLCR , allowing for the convenient assessment of PK-PD relationships for HCTZ when given alone or in combination with other agents used to treat fluid overload conditions.

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Pharmacokinetics of the thiazide diuretics

Cited by 56 publications

References 107 publications

Saturable Accumulation and Diuretic Activity of Hydrochlorothiazide in the Isolated Perfused Rat Kidney

Saturable Accumulation and Diuretic Activity of Hydrochlorothiazide in the Isolated Perfused Rat Kidney

Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

Population‐based meta‐analysis of hydrochlorothiazide pharmacokinetics

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