Microzide
Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin.

Williams RL, Davies RO, Berman RS, Holmes GI, Huber P, Gee WL, Lin ET, Benet LZ.

It is known that nonsteroidal antiinflammatory drugs such as indomethacin can attenuate the pharmacologic effect of loop diuretics such as furosemide and ethacrynic acid and that indomethacin may also reduce the pharmacologic response to chlorothiazide. To examine further this potential drug-drug interaction, we administered 50- an 100-mg single oral doses of hydrochlorothiazide with and without indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin either on the pharmacokinetics of hydrochlorothiazide or the pharmacologic response to this diuretic. The adsorption and disposition of hydrochlorothiazide demonstrate that this drug is rapidly absorbed and produces a diuretic and natriuretic response that peaks at approximately 2 hours after dosing and is essentially terminated 12 hours after dosing. There appeared to be no greater pharmacologic response to the 100-mg than to the 50-mg hydrochlorothiazide dose in the ten subjects in this study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7061724&dopt=Abstract hydrochlorothiazide Microzide



Microzide
Pharmacokinetics of hydrochlorothiazide in fasted and nonfasted subjects: a comparison of plasma level and urinary excretion methods.

Barbhaiya RH, Craig WA, Corrick-West HP, Welling PG.

The bioavailability of hydrochlorothiazide from 50-mg oral tablet doses was examined in healthy male volunteers under fasting and nonfasting conditions. Bioavailability was examined from plasma levels and urinary excretion of unchanged drug. The pharmacokinetics of hydrochlorothiazide in plasma could be described in terms of a triexponential function, and the mean drug half-lives determined from the three exponents were 1.0, 2.2, and 9.0 hr. Changing the accompanying fluid volume has no significant effect on hydrochlorothiazide absorption in fasted subjects. Plasma drug levels were significantly reduced in non-fasted individuals, compared with those in fasted individuals. A similar trend was observed in the urinary excretion of hydrochlorothiazide, but differences between treatments were not significant (p greater than 0.05). Mean 48-hr urinary recovery of hydrochlorothiazide was 70.5% of the dose in nonfasted subjects, and 73.5 and 75.0% of the dose in fasted subjects receiving the drug with 20 and 250 ml of water, respectively. The cumulative urinary excretion of hydrochlorothiazide correlated poorly (r = 0.27) with areas under plasma drug level curves, although the correlation between the means of these values for each of the three treatments was high (r = 0.996).. Close similarity was observed between urinary excretion rates of hydrochlorothiazide and the time course of drug concentrations in plasma.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7062255&dopt=Abstract hydrochlorothiazide Microzide



Microzide
The effect of cholestyramine and colestipol on the absorption of hydrochlorothiazide.

Hunninghake DB, King S, LaCroix K.

The effect of cholestyramine and colestipol on the absorption of a single orally administered dose of 75 mg hydrochlorothiazide was determined. Both urinary excretion and plasma levels of hydrochlorothiazide were measured. Cholestyramine or colestipol administration decreased the total urinary excretion of hydrochlorothiazide by 85 and 43%, respectively. Similar effects were also noted on plasma hydrochlorothiazide levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7076343&dopt=Abstract hydrochlorothiazide Microzide



Microzide
Inhibition of COX-2 counteracts the effects of diuretics in rats.

Kammerl MC, Nusing RM, Richthammer W, Kramer BK, Kurtz A.

Institut fur Physiologie I, Universitat Regensburg, Universitatstrasse 31, 93053 Regensburg, Germany. martin.kammerl klinik.uni-regensburg.de

BACKGROUND: It is well established that the diuretic- and renin-stimulated effects of loop diuretics can be attenuated by nonselective cyclooxygenase inhibitors. Since it is yet unclear which of the isoforms of cyclooxygenases, COX-1 and COX-2, is relevant in this context, our study aimed to determine the effects of selective COX-2 inhibition on the renal effects of the loop diuretic furosemide, as well as the diuretic hydrochlorothiazide, which acts on the distal tubule. METHOD: Male Sprague-Dawley rats were treated with furosemide (12 mg/day subcutaneously by osmotic pump) or hydrochlorothiazide (30 mg/kg body weight/day orally by gavage). In addition, parallel groups received rofecoxib (1 to 10 mg/kg body weight/day) for selective inhibition of COX-2. Controls were treated with vehicle. RESULTS: Induction of COX-2 mRNA expression due to furosemide was paralleled by increased renal excretion of prostanoids. Also, hydrochlorothiazide led to a rise in prostanoid excretion. Rofecoxib blunted the diuretic-induced increase in prostanoid excretion, thus confirming an effective blockade of COX-2. Moreover, the COX-2 inhibitor rofecoxib dose-dependently attenuated diuresis and saluresis, as well as the stimulation of the renin system induced by furosemide. Furthermore, rofecoxib completely reversed diuresis and saluresis and prevented the increase of plasma renin activity induced by hydrochlorothiazide. CONCLUSIONS: These findings suggest that COX-2-derived prostanoids are of major relevance in modulating the renal effects of diuretics. COX-2 inhibitors might be valuable drugs to treat salt and water wasting during Bartter and Gitelman diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11703585&dopt=Abstract hydrochlorothiazide Microzide



Microzide
Kinetics of allopurinol after single intravenous and oral doses. Noninteraction with benzbromarone and hydrochlorothiazide.

Breithaupt B, Tittel M.

An high-pressure liquid chromatographic method was used to measure allopurinol and oxipurinol in plasma and urine in 6 healthy volunteers after a single intravenous or oral dose of allopurinol. The influence of coadministered benzbromarone and hydrochlorothiazide on the pharmacokinetics of allopurinol and oxipurinol was also investigated. After intravenous injection of allopurinol 300 mg the plasma disappearance was biexponential, with a mean distribution half-life of 2.32 +/- 1.08 min (mean +/- SD) and an elimination half-life of 47.8 +/- 10.6 min. The total clearance of allopurinol was 11.37 +/- 2.70 ml/min/kg, whereas its renal clearance was only 1.73 +/- 0.79 ml/min/kg. Oxipurinol disappeared monoexponentially from plasma with a mean half-life of 12.2 +/- 2.6 h. Its renal clearance was 0.42 +/- 0.091 ml/min/kg. After oral administration of allopurinol 300 mg the peak plasma concentration of 2.1 +/- 0.6 micrograms/ml (1.5 x 10(-5) M) was reached within 30 to 120 min. The peak level of oxipurinol of 5.8 +/- 1.5 micrograms/ml (3.8 x 10(-5) M) was found within 2 to 5 h after intravenous and oral allopurinol. The bioavailability of oral allopurinol computed from plasma data was 90.4 +/- 8.7%. The total recovery from urine was 77% (allopurinol 8%, oxipurinol 69%) after oral and 88% after i.v. administration. It was concluded that about 10% of the oral dose was not absorbed and that 12% was eliminated by an unknown mechanism, presumably as riboside. The pharmacokinetics of allopurinol and oxipurinol were not significantly influenced by coadministration of benzbromarone or hydrochlorothiazide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7094977&dopt=Abstract hydrochlorothiazide Microzide