Journal of lnternal Medicine 1990; 227: 329-37

Nifedipine as an antihypertensive drug in patients with renal failure - pharmacokinetics and effects

I. ODAR-CEDERLOF, P. ANDERSON* & U. BONDESSON*t From the Department o/ Medicine, the *Departments o/ Clinical Pharmacology and Clinical Physiology. Karolinska Hospital. Stockholm. and the t Psychiatric Research Center, Uller6ker Hospital, Uppsala. Sweden

Abstract. Odar-Cederlof I, Anderson P. Bondesson U (Department of Medicine. Departments of Clinical Pharmacology and Clinical Physiology, Karolinska Hospital, Stockholm, and Psychiatric Research Center, Ulleriker Hospital, Uppsala. Sweden). Nifedipine as an antihypertensive drug in patients with renal failure - pharmacokinetics and effects. Journal of lnternal Medicine 1990: 227: 329-37.

Pharmacokinetics and pharmacodynamics of nifedipine were studied in 12 patients with renal failure and hypertension, after a single dose and during an 18-week treatment period.

The plasma concentrations of nifedipine and its first pyridine metabolite were measured by gas chromatography mass spectrometry. The oral plasma clearance of nifedipine was 1189 If: 876 ml min-', and the mean plasma half-life (ti) was 5.99 3.05 h. The pyridine metabolite was not retained. Plasma concentrations of nifedipine were found to be significantly correlated with the effects on blood pressure, forearm blood flow and peripheral resistance, and these effects did not vary with the degree of renal failure. Normotension was achieved in eight of the nine patients observed over a period of 4 months with doses in the range 2 0 4 0 mg, administered twice daily. The mean Cr-EDTA clearance remained unchanged during the study (initial value 3 1.4f 12.3 ml min-': final value 32.7 f 14.4 ml min-'), and in three patients it increased.

Nifedipine induces a slight increase in metabolic rate in patients with renal failure, but it is not necessary to modify the dose. It is effective in lowering blood pressure, has mild side-effects and may improve renal function in some patients.

Keywords: calcium channel blockers, kidney failure, nifedipine. pharmacodynamics, pharmacokinetics.

Introduction unmetabolized nifedipine. Reports on the pharmaco- kinetics of nifedipine in renal failure are few and

Pharmacological treatment of hypertension in inconsistent [ 7-91. The present study was under- patients with renal failure is essential. For many taken to elucidate possible changes, after admin- drugs, doses must be adjusted to kidney function due istration of a single dose and at steady state, of the to altered pharmacokinetics or pharmacodynamics pharmacokinetics and pharmacodynamics of nife- [l-31. Therefore all drugs used to treat patients with dipine in patients with impaired renal function and renal failure should be carefully studied with regard hypertension. to the possible effect of renal function impairment on their pharmacokinetics and pharmacodynamics, as well as their potential effects on renal function. Materials and methods

The calcium blocking agent nifedipine is a dihydro- Patients pyridine derivative. It is first oxidized and then hydrolysed to a new metabolite which is further Twelve patients with varying degrees of renal failure oxidized [4-61. The final metabolites are found in and hypertension, defined as systolic blood urine together with a small amount (0.1 %) of pressure > 160 mmHg and diastolic blood pressure

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NIFEDIPINE AND RENAL FAILURE 331

> 95 mmHg, participated in the study. Patient characteristics are shown in Table 1. The mean age of subjects was 54 years. The renal function was estimated by Cr-EDTA clearance, which had a mean value of 28 ml min-' (range 1 0 4 6 ml min-').

The mean blood pressure values were as follows : supine systolic, 189 f 1 7 mmHg ; supine diastolic, 1 0 8 f 8 mmHg; standing systolic, 177f 19 mmHg; standing diastolic, 104 & 8 mmHg.

One patient was untreated. Eleven patients were not sufficiently controlled on current therapy when they entered the study, and continued previous treatment with diuretics and/or beta-blocking agents, nifedipine being administered as an additional drug. In the one previously untreated patient nife- dipine was used as sole therapy. The treatment goal was normotension defined as supine blood pres- sure < 160/90 mm Hg. Nifedipine was given as 20 mg tablets twice daily. If necessary, the dose was titrated to 40 mg twice,daily. The duration of the study was 18 weeks.

Effect registration

Blood pressure was measured in the supine position after resting for 10 min and after standing for 2 min. The same nurse measured blood pressure on all occasions in the same arm using a mercury man- ometer. Mean values of three measurements were used. After the first dose, and at the middle of the study period, the effects of nifedipine on forearm blood flow, peripheral resistance and blood pressure were measured using venous occlusion pletysmo- graphy [lo]. Vascular peripheral resistance was calculated as the ratio of mean arterial blood pressure to forearm blood flow. Mean blood pressure was calculated as diastolic pressure plus one-third of the systolic-diastolic pressure difference.

At the same time as these determinations, venous blood samples were drawn, protected from the light, at fixed time intervals after the dose intake, for analysis of nifedipine and its initial metabolite, Plasma was separated and stored frozen at - 70 "C for further analysis. Cr-EDTA clearance was de- termined before and at the end of the study period.

Methods of synthesis and analysis

Synthesis of 2H, nifedipine. Nifedipine (0.5 g, 1.5 mmol) was stirred with 100 pl of concentrated sulphuric acid (isotopic purity 99.5%) in 40 ml of

trideuteromethanol in an air-tight bottle for 20 h at 50 "C. The solvent was evaporated and, after re- peating this procedure once, the crude residue was purified by thin layer chromatography (TLC) using toluene : methanol (9 5 : 5 by volume) as the mobile phase on a silica gel.

Mass spectrum analysis and NMR of the isolated product showed replacement of six protons at the 3- and 5-methyl ester moieties with deuterium atoms. The ratio ofm/z 333, 334, 335 (base peak), 336 and 337 was calculated to be 0.07, 0.32, 1.00, 0.25 and 0.18, respectively. No peak was observed at m/z 329, the base peak for nifedipine.

Method of analysis

All sample handling and extraction procedures were performed under gold fluorescent lighting (General Electric, F40GO) to prevent light degradation of nifedipine. Nifedipine and the metabolite BAY B4 7 5 9 (dimethyl 2.6-dimethyl-4-( 2-nitrophenyl)-3.5-pyri- dine dicarboxylate) were obtained from Bayer AG, Leverkusen, W. Germany.

To 1 ml of plasma was added :LOO pl of internal standard solution, consisting of 2.5 pg of 2H,-nife- dipine in 10 ml of methanol. The sample was gently mixed and 4 ml toluene and 1 ml of 0.1 M sodium hydroxide were added. The tube was tightly capped and its contents mixed for 15 min and centrifuged at 1000 g at room temperature. The organic phase was transferred to another tube, and the contents were evaporated in a stream of nitrogen at 50 "C. The residue was reconstituted with 50 p1 of ethyl acetate. Aliquots of 2 pl were injected for gas chromato- graphic mass spectrometry analysis. A calibration graph (0-200 ng ml-') was prepared by adding known amounts of nifedipine and BAY B4759 to drug-free plasma, and the samples were analysed as described above. A Finnigan Model 9610 gas chromatograph (Finnigan, Sunnyvale, CA, USA) was equipped with a SE-30 fused silica capillary column (Orion, Separation Research, Finland), 12 x 0.31 mm I.D. The column temperature was set at 250 "C. Injection of the samples was carried out using a solventless injection technique. The interface oven and transfer line were operated at 280 "C. Helium was used as carrier gas, with a flow rate of 1.5 ml min-'. A quadruple mass spectrometer (Finni- gan 4500) was operated in the electron impact mode with an ionization energy of 35 eV. The temperature of the ion source was set at 280 "C. The mass

332 I. ODAR-CEDERLOF et al.

spectrometer was adjusted to record the ions m/z = 329 for nifedipine, m/z = 335 for the internal standard and m/z = 289 for the metabolite. All the GC-MS data were collected, stored and processed using the INCOS 2300 Data System (Finnigan, Sunnyvale, CA, USA).

The calibration graph showed good linearity in the concentration range used, from 0-200 ng ml-l of both nifedipine and BAY B49 5 7. Nifedipine, added to drug-free plasma to give final concentrations of 5 ng ml-' and 100 ng ml-l, gave relative standard deviations of 5.9% ( n = 10) and 3.7% ( n = lo), respectively. There was no difference between normal and uraemic plasma. The lower limits of detection were 1.0 ng ml-' for both nifedipine and the metab- olite.

Pharmacokinetic calculations

The plasma concentration data for both nifedipine and the metabolite formed were treated according to a one-compartment model. The area under the plasma concentration-time curve (AUC) was esti- mated by the log-trapezoidal method, and the area to infinite time beyond the last sampling time after single-dose administration was added by integration (Ctn/k), where Ctn is the last concentration point on the regression line of the terminal phase of the plasma concentration curve. The elimination rate constant (k) of the last terminal phase of the curve was calculated by linear least-squares regression analysis. The plasma half-life of elimination was expressed as I n 2/k. The apparent oral plasma clearance (Clpl) of nifedipine was calculated as dose/AUC and the apparent oral volume of dis- tribution (Vd) as Clpl/k. An oral bioavailability of unity was thus assumed. The pharmacokinetic calcu- lations were performed by the ALEX program run on an Amdahl computer at the Stockholm Computer Center (QZ).

The relationships between the plasma concen- trations of nifedipine and the haemodynamic effects were assessed by means of a linear model (X = plasma concentration, Y = effect parameter). For each patient the regression coefficient was determined, and the relationship was tested by the sign test.

Blood glucose, serum cholesterol, triglycerides and uric acid were determined at the beginning and end of the study using routine methods, at the Department of Clinical Chemistry.

All patients who participated in the study had given their informed consent, and the investigation was approved by the Committee on Ethics at the Karolinska Hospital.

Results

Pharmacokine tics

The mean plasma concentrations of nifedipine and its pyridine metabolite (dimethyl 2.6-dimethyl-4-(2- nitrophenyl)-3.5-pyridine dicarboxylate) vs. time after the first dose are shown in Fig. 1. The elimination took place without evidence of a dis- tribution phase for any of the compounds. The pharmacokinetic data are presented in Table 2. The plasma half-life of nifedipine was 5.99k3.05 h, corresponding to an apparent oral plasma clearance of 1.08 & 1.00 1 kg-' h-'. The mean plasma half-life of the metabolite was 5.08 f 2.92 h.

Figure 2 shows the plasma profile for nifedipine and the metabolite during steady-state conditions. In six patients the maximum nifedipine and pyridine meta- bolite concentrations achieved were slightly higher during steady state than after the first dose. In the

loor I T

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Fig. 1. Plasma concentrations (mean values & SE) of nifedipine (0 --- 0 ) and its nitropyridine metabolite (0 --- 0) after administration of the first dose (20 j ig ) .

NIFEDIPINE AND RENAL FAILURE 3 3 3

Table 2. Pharmacokinetic data: mean valueskSD are shown

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Half-life (h) 5 . 9 9 k 3 . 0 5 5 . 0 8 k 2 . 9 2 7 . 3 7 k 7 . 2 6 6 .69+3.72 Volume of distribution 7.3 k 5 . 5 - 1 3 . 9 k 1 4 . 4 -

(1 kg-') Plasma clearance (I kg-' h-') 1.08 k 1.00 - 2 . 7 1 k 3 . 8 2 -

Plasma clearance (ml min-') 11 89 876 - 2 8 0 5 k 3 4 2 6 - *AUC (h ng ml-') 4 5 7 k 3 3 6 1 8 3 k 8 1 3 8 5 k 3 5 7 1 2 1 k 6 1

* AUC = area under plasma concentration-time curve.

- 0 6 12

Time (hours) Fig. 2. Plasma concentrations (mean values SE) of nifedipine (A---A) and its nitropyridine metabolite (A---n) at steady state.

whole patient group, the AUC for both nifedipine and the metabolite tended to decrease during steady state compared to the first dose administration, although the difference was not statistically significant (Table 2 ) . The mean oral plasma clearance of nifedipine increased after multiple dosing, although again this was not statistically significant (Table 2 ) .

Effects

Following the first dose of nifedipine, the systolic and diastolic blood pressure decreased significantly from

Systolic 165 - f 155 I 7 ] L * .11 141 blood pressure

: 120

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Fig. 3. Forearm blood flow, peripheral resistance, systolic and diastolic blood pressure (mean values k SI!) after the fmt dose (20 ms).

1 h onwards. Peripheral resistance was reduced significantly from 1.5 h, while forearm blood flow increased (Fig. 3 ) . These effects were most pro- nounced at the highest plasma concentrations of nifedipine, and were found to be less marked during steady-state conditions (Fig. 4).

The magnitude of the effects correlated with plasma concentrations of nifedipine. The mean cor- relation coefficient was - 0.68 5 for systolic blood pressure and - 0 . 3 75 for diastolic blood pressure.

334 I. ODAR-CEDERLOF et al.

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Table 3. Etrect on blood pressure: mean valueskSD are shown

Blood pressure (mmHg)

Week 0 Week 6 Week 18

Systolic supine 1 8 9 k 1 7 149+8*** 153 + 8***

Systolic standing 1 7 7 k 1 9 132*10*** 139*7*** Diastolic standing 104 * 8 86 k 6*** 90 k 6"

Diastolic supine 108+8 89f4*** 93 k 3"'

** 0.01 > p > 0.001. ***p < 0.001.

Thus the mean decrease in systolic blood pressure was 6.85 mmHg/lO ng nifedipine/ml plasma. The mean decrease in diastolic blood pressure was 3.75 mmHg/lO ng nifedipine/ml plasma. The mean correlation coefficient was 0.337 for forearm blood flow and 0.0039 for peripheral resistance. The relationship between nifedipine concentrations and pharmacodynamic effects was statistically significant

During the subsequent treatment period one patient was omitted due to lack of co-operation (refused further blood sampling). In the remaining

(P < 0.001).

Before After treatment treatment

Fig. 5. Cr-EDTA clearance before and after 18 weeks of treatment in the nine patients who completed the study.

patients, the blood pressure decreased significantly during treatment (Table 3). Normotension was achieved at week 4 in 10 patients: in one patient the diastolic blood pressure only decreased to 9 5 mmHg ; however, this represented a decrease of 20 mmHg. and his systolic blood pressure was normal. The following doses were used after titration: 40 mg daily in seven patients, 60 mg daily in two patients and 80 mg daily in three patients. The blood pressure was slightly higher at week 18 than during the early phase of treatment (Table 3). Two patients ex- perienced side-effects, headache and ankle oedema, respectively, which they found so disturbing that they stopped medication after 5 and 9 weeks, respectively. The remaining nine patients completed the study protocol, and did not experience any side- effects. The levels of fasting blood glucose, cholesterol, triglycerides and uric acid remained unchanged.

Cr-EDTA clearance did not change during treat- ment, the mean value being 32.7f 14.4 ml min-' at week 18 compared to 31.4 f 12.3 ml min-' before treatment. In three patients Cr-EDTA clearance increased, and in five patients it remained unchanged (Fig. 5). In one patient Cr-EDTA clearance decreased from 29 to 25 ml min-'; in this individual there was rapid progress of the chronic glomerulonephritis. verified as IgA nephritis at biopsy, during the months following the study.

NIFEDIPINE A N D R E N A L FAILURE 335

Discussion

Pharmacokinetics

In patients with renal failure, the mean plasma half- life of nifedipine was 5.99 f 3.05 h, a value similar to that found in normal subjects given 20 mg tablets as a single oral dose (5.2f0.6 h) [ l l ] , (5 .9f0.9 h) [ 121. However, in one study a longer plasma half-life was observed in normal subjects (10.8 f 2.4 h) taking 20 mg tablets as a single oral dose [13]. The apparent oral plasma clearance rate in the present study (1 189 f 8 76 ml min-') is higher than that reported for subjects with normal renal function (5 5 3 f 12 1 ml min-', corresponding to apparent oral plasma clearance rates of 8 5 1 f 186 ml min-' and 11 .2k1 .0 ml min-' kg-') [ l l , 131. This finding may indicate a slightly higher metabolic rate in patients with impaired renal function, which would be consistent with earlier studies. For example, anti- pyrin, which is representative of drugs that are predominantly metabolized by oxidation [ 141, was found to have a shorter half-life in patients with impaired renal function than in controls. The mech- anism proposed is enzyme introduction by toxic endogenous substances that accumulate during renal failure.

Earlier studies on the pharmacokinetics of nife- dipine in renal failure have yielded conflicting results. Kleinbloesem et al. found that the kinetics of nife- dipine administered as tablets were not influenced by the degree of renal failure [7]. After intravenous administration of nifedipine, however, the plasma half-life was longer, the apparent volume of dis- tribution larger, but total systemic clearance un- changed in patients with renal failure compared to controls. In patients undergoing treatment with nifedipine, plasma levels were unchanged in pre- dialysis patients, but were decreased in haemodialysis patients compared to normal subjects [8]. Martre observed similar pharmacokinetics for nifedipine in haemodialysis patients and controls [9]. There have been no previous studies on the metabolites of nifedipine in renal failure. We have earlier shown that the plasma levels of both intermediary and final drug metabolites can rise to levels far higher than normal in patients with renal failure [15]. The present study shows that the nitropyridine metab- olite of nifedipine is not retained.

There was a tendency for plasma clearance of nifedipine to be greater during steady state than after

a single dose, but the difference was not statistically significant. The variations between individuals were large, as was also the case for normal subjects and haemodialysis patients [ 5-71. In addition, blood pressure values were slightly higher at week 18 than at week 6.

Eflects

A satisfactory blood-pressure-lowering effect was obtained in all patients who completed the study. A hypotensive effect of nifedipine in patients with chronic renal failure and hypertension has also been documented by other authors [ 16-1 81. In the present study, only two subjects experienced side-effects, namely headache and ankle oedema. Both are well- known reactions to calcium channel blockers and, although disturbing, are not serious.

Eleven patients were given nifedipine as an ad- ditional treatment to previous therapy with diuretics and/or beta-blocking agents. This does not represent an ideal situation for the study of pharmacodynamics and pharmacokinetics. However, while on treatment these patients had hypertension of a degree that did not allow withdrawal of previous drug therapy before entering the study. They are representative of patients with renal disease in whom the hypertension is generally severe and requires treatment with more than one drug. In clinical practice, therefore, nife- dipine will be used in combination with other antihypertensive agents in the treatment of patients with renal failure, as was reported for the present study.

Plasma levels of nifedipine were correlated with the effect on blood pressure, forearm blood flow and peripheral resistance in our patients. A relationship between plasma nifedipine concentrations and effects has also been found in hypertensive patients with normal kidney function and in those with renal failure [7, 19, 201. Kleinbloesem et al. observed an inverse correlation between the maximal effect on diastolic blood pressure and creatinine clearance [7]. The practical implication of such a finding would be reduction of doses in patients with renal failure. However, our study showed no dependence of effect on renal function, either after a single oral dose or during steady state. In accordance with this result, our patients required doses similar to those used to obtain normotension in hypertensive subjects with normal kidney function.

For the whole group, renal function was unaltered

336 I. ODAR-CEDERLOF et al.

during the 18-week observation period. None of the patients experienced a sudden decrease in renal function such as has been described in a few cases [21, 221. On the contrary, the glomerular filtration rate increased in three patients. Earlier acute studies have shown that nifedipine increases renal plasma flow and glomerular filtration rate and decreases renal vascular resistance in patients with essential hypertension [2 3-2 61. Animal experiments have shown that calcium blocking agents decrease renal vascular resistance, and counteract the vasocon- strictor effect of angiotensin 11, norepinephrine or vasopressin, as well as increasing the glomerular filtration rate [27-311. Eliahou et al. found that long-term treatment with nifedipine delayed the progression of renal function impairment in patients with renal disease [32]. Thus calcium blocking agents such as nifedipine, like ACE inhibitors but in contrast to beta blockers, might have a potentially advan- tageous effect on renal function.

No metabolic effects of nifedipine on blood glucose or plasma lipids were observed in the present study. Calcium blocking agents might thus offer an ad- vantage over beta blockers and diuretics in the treatment of hypertensive renal patients who already suffer from disturbances of lipid and glucose metab- olism caused by renal failure.

In the present study, nifedipine has been shown to be a suitable antihypertensive drug for use in patients with renal failure. It has the effect of lowering blood pressure significantly in patients for whom diuretics or beta blockers have unsatisfactory effects when given as additional therapy, it has mild side-effects and no adverse effect on renal function. Neither nifedipine nor its pyridine metabolite are retained. Thus there is no pharmacokinetic or pharmaco- dynamic evidence for dose adjustment in renal failure.

Acknowledgements This work was supported by a grant from the Karolinska Institute.

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Received 12 September 1989. accepted 5 October 1989.

Correspondence : I . Odar-Cederlof, MD. Department of Medicine, Karolinska Hospital, S-I04 0 1 Stockholm, Sweden.