Bioavailability and Pharmacokinetics of Isradipine after Oral and Intravenous Administration: Half-Life Shorter than Expected?

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1 C Pharmacology & Toxicology 2000, 86, Printed in Denmark. All rights reserved Copyright C ISSN Bioavailability and Pharmacokinetics of Isradipine after Oral and Intravenous Administration: Half-Life Shorter than Expected? Hanne Rolighed Christensen, K. Antonsen, K. Simonsen, A. Lindekær, J. Bonde, Helle Riis Angelo and Jens P. Kampmann Unit of Clinical Pharmacology, Department of Clinical Biochemistry, Bispebjerg University Hospital Copenhagen and Department of Intensive Care Medicine, Herlev University Hospital Copenhagen, Denmark (Received May 26, 1999; Accepted November 9, 1999) Abstract: Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8 9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies. Isradipine, a dihydropyridine calcium channel-blocking agent, elicits potent vasodilation of the systemic vascular bed without causing any significant cardiodepression (van Wijk 1989). Clinical experience has shown that isradipine administered orally in doses from 1.25 to 2.5 mg b.i.d. as tablets or 5.0 mg once daily in a sustained release formulation has an effect on blood pressure equal to that of other antihypertensive drugs (Fitton & Benfield 1990; Christensen et al. 1991). The terminal half-life of isradipine after oral studies is reported to be about 8.8 hr (Fitton & Benfield 1990). In yet unpublished studies we have observed a significantly shorter half-life (2.5 hr) following intravenous administration of isradipine to patients with pregnancy-induced hypertension. To elucidate if this apparent discrepancy was caused by methodological differences (oral versus intravenous administration) or due to physiological differences induced by pregnancy we conducted this trial to evaluate isradipine kinetics after intravenous infusion and oral administration to healthy volunteers. Materials and Methods Ten healthy normotensive volunteers, (3 women, 7 men) mean age 24.2 years, and mean weight 71.9 kg were included in the study (table 1). All the subjects had serum concentration values of haemoglobin, potassium, sodium, creatinine and liver enzymes within normal range. Table 1 shows characteristics of the individual volunteers. A volunteer was excluded if blood pressure before study start was Author for correspondence: Hanne Rolighed Christensen, Engbakken 4, DK-2830 Virum, Denmark (fax π ). below 110/60 mmhg, if blood had been donated within the last 2 months, or if drugs of any kind were used. All volunteers gave written informed consent, and the study was approved by the Local Ethics Committee, the Danish Health authorities and was performed in agreement with the Helsinki declaration. Design. In a randomised cross-over fashion the volunteers were given isradipine as an infusion as well as orally. Half of them started with an infusion of isradipine followed by oral treatment, while the other half were given isradipine orally followed by the infusion. The two study periods were separated by at least 3 days. A light breakfast was allowed on study days. Blood pressure, pulse-rate and ECG (3 leads) were registered continuously during the first 6 hr at the two examinations. Administration of isradipine. In order to minimize the distributing phase to interfere with the kinetic datahandling, we decided to use an infusion regimen. In an attempt to achieve a steady-state concentration level of 5 8 mg/l (therapeutic level in man) (Fitton & Benfield 1990) and considering that the participants were normotensive, we reached the infusion regimen outlined below. Isradipine infusion. One mg isradipine was given intravenously at a constant rate during 60 min. Then the infusion rate was decreased to a constant infusion rate of 300 mg isradipine hr for the next 3 hr. Blood samples for the isradipine measurement were collected at: 0, 15 min., 30 min., 45 min., 60 min., 90 min., 2 hr, hr,3hr,31hr, 2 4hr,4 1 2 hr,5hr,51 2 hr, 6 hr, 7 hr, 8 hr, 9 hr, 10 hr. This design was expected to give a reliable estimate of the terminal half-life. In addition concentrations measured late would be around or below the limit of quantitation (see below). Oral treatment. Each patient received isradipine sustained release capsules (Lomir Retard) 5.0 mg b.i.d. for 3 days (steady state). On the fourth day, and after intake of the last capsule, blood samples for isradipine measurement were collected over 12 hr (one dosage interval) in the following way: time 0 (just before drug intake), 1 2 hr,

2 ISRADIPINE PHARMACOKINETICS 179 Table1. Characteristic features of the volunteers at the start of the experiments. Weight Height BP sys BP dia No. kg cm Age mmhg mmhg Sex m m m m f m m f m f mean hr,1 1 hr, 2 hr, 2 21 hr, 3 hr, 2 31 hr, 4 hr, 2 41 hr, 5 hr, 2 51 hr, 6 hr, hr,7hr,7 1 2 hr, 8 hr, 9 hr, 10 hr, 11 hr and 12 hr after administration. Isradipine analysis. Blood samples for the determination of serum isradipine were separated after centrifugation and frozen at 20æC until assayed. Serum isradipine was analysed by a sensitive gas chromatographic method with a quantitation limit of 0.5 nm (0.2 ng/ ml) and an interassay coefficient of variation of %, (Christensen et al. 1992). Statistics. The results are given as arithmetic means and standard deviation, medians and ranges. The pharmacokinetic parameters after the infusions were calculated with the TOP FIT computer software (version 2.0) using a non-compartmental model. The AUCøs were calculated after the oral administration in a dosing interval by the trapezoidal rule. Bioavailability was calculated as the ratio between AUC (oral)/ dose and AUC (intravenous) corrected for dose. Results The present analysis includes 10 volunteers who all completed the study. Representative plasma concentration-time profiles after intravenous infusion of and oral treatment with isradipine are shown in fig. 1 and 2, while table 2 summarises individual kinetic data after intravenous and oral administration. Isradipine concentrations reached C max of 6.3 mg/l 0.78 hr (t max ) after intravenous infusion. In most cases the plasma concentration curves indicated that steady-state was achieved during the infusion period, as a plateau was reached during the last 2 hr (fig. 1). The plateau, however, was reached at a lower level than expected. The median terminal half-life was estimated to 2.80 hr (range 1.96ª5.73) after the intravenous administration. Clearance was 1918 ml/min. (113 l/hr) 559 (34 l/hr) (mean and SD), volume of distribution 553 l 249 and bioavailability (mean and S.D.). Oral treatment as well as intravenous infusion of isradipine were well tolerated by all volunteers and there were no side effects or adverse haemodynamic reactions. Discussion Several studies on the pharmacokinetics of isradipine after oral administration have been published (Tse & Jaffe 1987; Clifton et al. 1988; Chandler et al. 1988; Schran et al. 1988; Chellingsworth et al. 1988; Shenfield et al. 1990; Christensen et al. 1993), (table 3), while until now only one study has evaluated the kinetic parameters after intravenous ad- Fig. 1. Plasma concentration-time profile after intravenous infusion of isradipine (1 mg/hr the first hr, then 300 mg/hr for 3 hr).

3 180 HANNE ROLIGHED CHRISTENSEN ET AL. Fig. 2. Plasma concentration-time profile after isradipine capsules (retard formulation) 5.0 mg b.i.d. (steady-state). ministration (Carrara et al. 1994). No study with a similar design has been dealing with bioavailability. Oral administration only of radioactive labelled compounds have demonstrated a rapid and virtually complete absorption from the gastrointestinal tract with a mean t max of about 1.5 hr. However, isradipine undergoes extensive first-pass metabolism resulting in formation of 5 main pharmacological inactive metabolites (Fitton & Benfield 1990). The bioavailability (F) of isradipine is approximately 0.17 with radioactive labelled oral doses of 5 to 20 mg (Echizen & Eichelbaum 1986; Lobo et al. 1987). In these studies the serum concentration of isradipine has usually been measured by RIA. About 10 % of the drug is excreted unchanged in faeces. After oral administration, the terminal half-life varies from hr with a mean of 8.8 hr, (Fitton & Benfield 1990) (table 3). However, data from studies after intravenous administration have shown a half-life of about 3.0 hr (Carrara et al. 1994) and 3.3 hr (present study, table 2), which resembles results from earlier studies using an oral solution (half-lives: ) (Clifton et al. 1988). The difference in half-life after intravenous and oral administration suggests that absorption could still take place in the elimination phase after intake of capsules or tablets. Although the half-lives in these two intravenous studies are of identical orders of magnitude, a large difference has been observed in V d (volume of distribution) and Cl (clearance). The study by Carrara et al. (1994) demonstrated a Table 2. Pharmacokinetic data after oral (AUC and F) and intravenous infusion of isradipine. C max t max t 1 2 AUC iv AUC oral mikg/l hr hr mikg mikg V d Cl No (i.v.) (i.v.) (i.v.) *hr/l *hr/l F l l/hr mean S.D median range

4 ISRADIPINE PHARMACOKINETICS 181 Table 3. Pharmacokinetic data of other dihydropyridine calcium antagonists (18) Drug V d (l) Clearance (ml/min) t 1 (h) 2 Amlodipine Felodipine Nicardipine Nifedipine Nitrendipine V d of 27 l (mean) and Cl of 686 ml/min. while the present study suggests a V d of 553 l and Cl of 1918 ml/min. (113 l/ hr). This variance is difficult to explain. A V d of only 27 l seems too small for a lipophilic drug such as isradipine (Fitton & Benfield 1990). There is no consistence between dose, AUC and clearance (ClΩDose/AUC) in the study of Carrara et al. (1994) and very few details of the pharmacokinetic calculations have been described. The analysis of serum isradipine concentration differs between the two intravenous studies (gas chromatographic analysis in the present study and RIA in that of Carrara et al. (1994)). This may explain some of the differences as the RIA method co-dertermines metabolites and thereby overestimates the AUC compared to the chromatographic method. Due to the big difference between the result of Carrara et al. (1994) and the present study, the plasma samples have been re-analysed, and the infusion records have been re-examined without finding any errors. The clearance found in our study is very high for this hepatically eliminated drug. The clearance was calculated after intravenous infusion according to the formula: ClearanceΩDose/AUC where AUC is area under the concentration versus time curve. Clearance is overestimated, if the amount of isradipine in the body was less than expected from the dose given (AUC too small). Isradipine is known to adhere to certain plastic materials, and special tubes for infusion are recommended. The possibility for adhesion of isradipine to the infusion tubes used in the present study was tested, but no adhesion of isradipine to the plastic material was observed. Previous experience has shown that nitro-substituted dihydropyridine calcium channel blockers, such as nifedipine and nisoldipine, are very sensitive to daylight (Ahnoff & Persson 1990). Isradipine seems less lightsensitive, as no degradation was observed after exposure of a 1 mm solution of isradipine to daylight for one day (Christensen et al. 1992). Degradation of isradipine in plasma seems to be a more unlike possibility, as human plasma does not contain esterases, which could degrade (hydrolyse) the methyl- and isopropylester-bindings of isradipine (Tokuma et al. 1987). Isradipine, like some other dihydropyridines (Ahnoff & Persson 1990) increases the hepatic blood flow, which could explain the high clearance for isradipine found in this study. Isradipine was given in higher dose (1.9 mg/4 hr) in the present study compared to the other intravenous study (Carrara et al. 1994) (1.0 mg/5 min.) which could explain part of the difference in clearance (if clearance is flow-dependent). Another reason for the high clearance could be that the young volunteers in this study, with a majority of males, simply have a relatively high liver blood-flow. There is no evidence that extrahepatic metabolism could explain the clearance values, although isradipine like the other dihydropyridines are metabolised by CYP3A4, an enzyme not only present in the liver. The fact that the time to the mean maximal concentration after intravenous infusion, c max, is shorter than the infusion period with the high infusion rate may be explained by several factors, e.g. technical reasons like uncertainty of infusion rate and duration, blood sampling and analytical variance. Similarly, distribution into poorly perfused compartments due to the vasodilating effect of the compound may be the explanation, as may variance in clearance over the study period. It should be remembered that most kinetic studies are performed with relatively small sample sizes, and in the present study with a drug with low bioavailability and high variability in half-lives and other kinetic parameters, which contribute to the differences between the two studies. In conclusion, the half-life of isradipine in our intravenous study seems to be much shorter than demonstrated earlier in oral studies. Acknowledgements Payment of healthy volunteers and medication was kindly supplied by Sandoz A/S, now part of NOVARTIS Health Care A/S, Copenhagen. References Ahnoff, M. & B. Persson: Chromatography of calcium channel blockers. J. Chromatogr. 1990, 531, Carrara, V., H. Porchet & P. 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