Br. J. clin. Pharmac. (1979), 7, 579-583

PHARMACOKINETICS OF HYDROCHLOROTHIAZIDE IN PATIENTS WITH CONGESTIVE HEART FAILURE B. BEERMANN & MARGARETHA GROSCHINSKY-GRIND Department of Medicine and Clinical Pharmacology Laboratory, Serafimerlasarettet, S-1 1283 Stockholm, Sweden

1 Hydrochlorothiazide (HCT, 50-75 mg) was administered orally to seven patients with cardiac failure. 2 Plasma levels and urinary concentration of HCT were determined by GLC. 3 The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4 Plasma hailfife of HCT was correlated with endogenous creatinine clearance. 5 Pharmacokinetics of HCT are considerably changed in cardiac failure.

Introduction

Hydrochlorothiazide (HCT) is a widely prescribed diuretic, used in congestive heart failure and hypertension. In healthy fasting volunteers the gastrointestinal uptake of the compound approximates 70% and it is linear over the dose range 5-75 mg (Beermann, Groschinsky-Grind & Rosen, 1976; Bermann & Groschinsky-Grind, 1977). The plasma kinetics of HCT can be described by a two-compartment open model with a half-life of the P-phase ranging between 5.6 and 14.8 h when the plasma levels of HCT can be followed for at least 24 h. The drug is more than 95% eliminated in unchanged form via the kidneys and the renal clearance averages 330 m/min after 12.5 to 75 mg HCT. Peak plasma levels after 50-75 mg are reached after 1.5-4 h in fasting subjects. Cardiac failure might conceivably change the rate and extent of gastro-intestinal absorption of drugs by decreased intestinal motility, oedema in the intestinal wall and reduced blood flow (Benet, Greither & Meister, 1976). The aim of the present study was to investigate the fate of HCT in patients with congestive heart failure. Methods

Subjects Seven patients, described in Table 1, took part in the study. They were admitted for congestive heart failure to the medical department at the Serafimerhospital. Experimental procedure All patients were under treatment with a digitalis preparation. Four of the patients had also been treated with frusemide, which was changed to ethacrynic acid

(T. Edecrina, 50 mg, Merck, Sharp and Dohme, Rahway, N.J., USA) at least 24 h before the study. This was done because frusemide, but not ethacrynic acid, interferes with the GLC assay of HCT. On the day before the start of the study a chest X-ray was taken. Heart volume was calculated according to Jonsell (1939). On the day of the study, the patients had a physical examination and blood samples were taken for analysis of S-Hb, S-NA+, S-K+, S-albumine, Screatinine. Body weight was measured daily throughout the study. At 08.00 h the patients were administered 50 mg HCT, after fasting overnight (T. Esidrex 2 x 25 mg, Ciba Geigy Ltd, Basle, Switzerland). By mistake patient S.L. received three tablets of HCT, i.e. 75 mg. The subjects were allowed to drink, eat and smoke at wish in the afternoon. On the following days the patients were given ethacrynic acid in various doses. After the end of the study the patients were prescribed frusemide, hydrochlorothiazide or ethacrynic acid. Venous blood samples for determination of HCT were drawn twice an hour during the first 2 h, thereafter at each hour from 3-6 h and at 8, 10,24,26, 32,48, 53 and 72 h. The urine was collected at 0-12 and 12-24 h, and thereafter at 24 h intervals during the following 5 days. Urine was analyzed for HCT and creatinine. Immediately after sampling, plasma was separated from the blood cells by centrifugation at 325 g for 15 minutes. The plasma samples were stored at -200C until the day of analysis for HCT. Each series of plasma and urine was analyzed on the same day. The concentrations of HCT in plasma and urine were determined by GLC after extractive alkylation according to Lindstrom, Molander & Groschinsky-Grind (1975).

580

B. BEERMANN & MARGARETHA GROSCHINSKY-GRIND

The chemical examinations were performed at the Department of Clinical Chemistry at the Serafimerhospital. Pharmacokinetic analysis C XDD CD

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Linear regression analysis of the plasma concentration-time curve was performed after logarithmic transformation. The terminal elimination rate constant (k) and the plasma half-lives (Tj)were calculated. The area under the plasma concentrationtime curve (AUC) during the first 24 h was calculated by the trapezoidal rule. The renal clearance of HCT was estimated by dividing the urinary recovery of HCT during 24 h by the AUCO024 h#In one patient (S.P.) the plasma levels could be followed for lOh. The renal clearance was calculated on the urinary recovery during the first 12h and the AUC012hwhere the plasma concentration at 12 h was extrapolated.

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The peak plasma levels of HCT after 50 mg were seen at 1.5-8.0 h and ranged between 282 and 672 ng/ml. Patient S.P., who had the slightest heart failure, reached the highest and earliest plasma peak concentration. Her plasma concentration of HCT could only be followed for 10 h (Figure 1). Patient N.L. did not reach a plasma maximum until 8 h, when it amounted to 512 ng/ml. His and patient N.K.'s plasma concentrations of HCT could be followed for 72 h (Figure 1) and that of the other patients for 48 h. The terminal phase of the plasma curve of HCT in N.L. had a k-value of 0.0240 h-'. It appeared as ifthere was an a-phase but k could not be determined because of too few plasma samples from 8-24 h. The decline of the plasma curve showed a single phase in subjects S.P. and S.H. with k=0.2264 and 0.0776 h-i respectively. In subjects J.G., N.K. and G.N. a second slower phase became apparent at 8-10 h, the k of this phase being 0.0295, 0.0341 and 0.0342 h-i respectively and that of the a-phase 0.7284, 0.7951 and 0.2749 h-i respectively. Patient S.L. was given 75 mg HCT. The peak plasma level was seen at 4 h and amounted to 468 ng/ml. The elimination rate became slower after 12 h, k of the 0phase amounting to 0.0553 and that of the a-phase to

HYDROCHLOROTHIAZIDE KINETICS IN CARDIAC FAILURE

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Plasma concentration time curve after 50 mg HCT to patients NL (0) and SP (0).

Pharmacokinetic data obtained after 50 mg to 75 mg HCT orally, to patients with congestive heart

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581

B. BEERMANN & MARGARETHA GROSCHINSKY-GRIND

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0.4042 h-'. The half-life of HCT correlated with the endogenous creatinine clearance (P < 0.05). Urinary recovery of HCT (Table 3 and Figure 2). The total urinary recovery after 50 mg HCT ranged between 10.4 (20.8%) and 35.8 (71.6%) mg. No HCT could be traced in the last urinary portion. Patient N.L. failed to collect urine properly after the first 24 h. Subject S.L. excreted 39.8 mg (53%) after 75 mg HCT orally. The renal clearance of HCT ranged between 10 and 187 ml/min and a linear relationship was found between the endogenous creatinine clearance and the renal clearance (P< 0.05) of HCT. During the 7 days of the study the subjects lost a mean of 4.4 kg (range 1.5-6.0 kg).

Discussion The total urinary recovery after HCT orally reflects the gastrointestinal absorption. provided the time of collection is sufficiently long, as it has been shown that HCT is excreted in mainly unchanged form via the kidneys (Beermann et al., 1976). Andersson, Bretell & Aikawa (1961) observed reduced urinary recovery of label after oral administration of [14CJ-HCT to a group of patients with cardiac failure. However, urine was collected for only 24 h. Their results indicated a slower elimination of HCT in such subjects. The renal clearance of HCT in healthy volunteers averages 330 mVmin (Beerman & Groschinsky-Grind, 1977). The corresponding values in the present patients ranged between 10 and 187 mil/min. The decreased

excretion rate was explained by reduced renal function. In the present study the last urinary portion contained no HCT showing that the time of collection was long enough to allow an estimation of the uptake of HCT. In healthy volunteers, a mean of 65% of an oral dose of 50-75 mg HCT is recovered in the urine during 48 h (Beerman & Groschinsky-Grind, 1977). The recovery of 21-37% of the dose given to patients S.H., N.K. and G.N. indicates a substantially decreased absorption of HCT in these subjects. The late plasma peak in patient N.L. suggests that the absorption may also be delayed. The total urinary excretion of HCT in patients J.G. and S.L. approximated 50% of the dose, which is at the lower border of what can be regarded as normal. An incomplete collection of urine might partly explain the reduced urinary recovery. However, the patients were studied in a medical ward supervised by a staff trained in metabolic experiments. The absorption of HCT appears to be similar in the age groups 18-32 and 40-60 years (Beermann & Groschinsky-Grind, 1977). Our patients were older and it can not be excluded that the absorption of HCT was influenced by this. However, there appear to be no data available which demonstrate any influence of age on drug absorption per se, although age associated disorders such as achlorhydria might be relevant in this context The scarce literature on this topic indicates a need for studies on age and drug absorption. The mechanism behind the diminished absorption might be explained by changes in the intestinal wall and/or in blood flow, as the reduced intestinal mobility in cardiac failure should rather promote the uptake of the drug (Beermann & Groschinsky-Grind, 1978). The plateau of the dose response curve begins at dose levels of about 50 mg HCT orally in cardiac patients (Ford, 1959; Mertz, 1959; Meyer, Fuchs, Shinazo & Tibor, 1959), whereas in healthy volunteers it starts at lower doses (Beermann & GroschinskyGrind, 1977; Gilmore, O'Brian, Brand, Peach & Westfall, 1970). Part of this discrepancy might be explained by reduced gastrointestinal uptake in patients with congestive heart failure.

Mrs Annica Corestav, Ms Margaretha Hallingstrom and Anita Rehn are thanked for technical assistance, Miss Ann-

Marie Lothigius for drawing the graphs and Miss Kristina Rylander for typing the manuscript. This work was supported by the Swedish Medical Research Council (grant no. 77-19x-00227, 13)

References ANDERSSON, K.V., BRETELL, H.R. & AIKAWA, J.K.(196 1). '4C-labelled hydrochlorothiazide in human beings. Arch.

intern. Med., 107, 168-174. BEERMANN, B., GROSCHINSKY-GRIND, M. &

ROSMN, A.

(1976). Absorption, metabolism and excretion of [(4C]hydrochlorothiazide. Clin. Pharmac. Ther., 19, 53 1-537. BEERMANN, B. & GROSCHINSKY-GRIND, M. (1978).

HYDROCHLOROTHIAZIDE KINETICS IN CARDIAC FAILURE

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GILMORE, J.P., O'BRIEN, W.M., BRAND, E.D., PEACH, M.J.

heart size by teleroentgenography (a heart volume index). Acta Radiol., 20, 325-340. LINDSTROM, B., MOLANDER, M. & GROSCHINSKYGRIND, M. (1975). Gas chromatographic determination of HCT in plasma, blood corpuscles and urine using extractive alkylation technique. J. Chromatogr., 101, 219-221. MERTZ, D. (1959). Pharmakologische Eigenschaften von Hydrochlorothiazide im Vergleich zu Wirkung anderen Diuretika. Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 237,71-93. MEYER, J.K., FUCHS, M., SHINAZO, I. & TIBOR, B. (1959). Some observations on the pharmacology of hydrochlorothiazide. Am. J. Cardiol., 3, 113-117.

& WESTFALL, T.C. (1970). A student exercise in clinical pharmacology. Renal effects of diuretics. Curr. Ther. Res., 12, 750-769. JONSELL, S. (1939). A method for the determination of the

(ReceivedApril 11, 1978, Revised September 7,1978)

Enhancement of the gastrointestinal uptake of hydrochlorothiazide by propantheline. Eur. J. clin. Pharmac. 13, 195-202. BEERMANN, B. & GROSCHINSKY-GRIND, M. (1977). Pharmacokinetics of hydrochlorothiazide in man. Eur. J. clin. Pharmac., 12, 297-303. BENET, L.Z., GREITHER, A. & MEISTER, w. (1976). Gastrointestinal absorption of drugs in patients with cardiac failure; in The effect of disease states on pharmacokinetics, ed. Benet, L.Z., pp. 33-50. Washington: American Pharmaceutical Association. FORD, R. (1959). The clinical pharmacology ofhydrochlorothiazide. South med. J., 52, 40-45.