Pharmacokinetics of Temocapril and Temocaprilat After 14 Once Daily Oral Doses of Temocapril in Hypertensive Patients with Varying Degrees of Renal Impairment

Br J Clin Pharmacol 1997; 44: 531–536

Pharmacokinetics of temocapril and temocaprilat after 14 once daily oral doses of temocapril in hypertensive patients with varying degrees of renal impairment

K. Pu¨chler,1 K. M. Eckl,2 L. Fritsche,3 K. Renneisen,1 H.-H. Neumayer,3 B. Sierakowski,1 A. T. J. Lavrijssen,4 T. Thomsen2 & I. Roots5 1Sankyo Europe GmbH, Duesseldorf, Germany, 2PharmPlanNET Contract Research GmbH, Moenchengladbach, Germany, 3Medizinische Klinik und Poliklinik V (Nephrology), Charite´, Humboldt University, Berlin, Germany, 4Oosterschelde Hospital Goes, The Netherlands, 5Institute of Clinical Pharmacology, University Clinic Charite´, Humboldt University, Berlin, Germany

Aims The aim of this study was to determine the potential influence of renal impairment on the pharmacokinetics of temocapril and its pharmacologically active diacid metabolite, temocaprilat. Methods Non-compartmental pharmacokinetics were assessed in four groups of hypertensive patients (n=8 per group, four investigational centres) with normal −1 (creatinine clearance determined via 24 h urine sampling, CLCR, ≥60 ml min ) −1 and impaired renal function (CLCR 40–59, 20–39, <20 ml min ) after 14 once daily oral doses of 10 mg temocapril hydrochloride. Results For temocapril, there were no statistically significant differences in median tmax or mean Cmax, AUCSS, tD,Z, CL/F between the four groups. Renal clearance, CL , for temocapril showed a linear decreasing trend with decreasing CL [mean R − CR (s.d.): 32.2 (10.7) to 3.7 (3.0) ml min 1]. Steady-state for temocaprilat was reached on day 5. For temocaprilat, no statistically significant differences in mean Cmax or median tmax were detected. With decreasing mean CLCR, mean AUCSS for temocaprilat increased statistically significantly although only 2.4-fold [mean (s.d.): −1 2115 (565) to 4989 (2338) ng ml h] and tD,Z was prolonged [mean (s.d.): 15.2 (1.2) to 20.0 (7.5) h]. CLR for temocaprilat showed a linear decreasing trend with −1 decreasing CLCR [mean (s.d.): 20.2 (4.3) to 3.0 (1.8) ml min ]. Conclusions These results indicate that impaired renal function has only a limited effect on the pharmacokinetics of temocapril and its active metabolite, temocaprilat. This may be attributed to the dual, i.e. renal and biliary, elimination pathway of the drug. Keywords: temocapril, temocaprilat, ACE inhibitor, renal failure, pharmacokinetics

through the alternative route [3, 4]. Because of this, the Introduction drugs can be administered without dosage adjustment to Angiotensin converting enzyme (ACE) inhibitors are a subjects with mild to moderate renal impairment. group of drugs that have assumed an increasingly prominent Temocapril (INN) hydrochloride is (+)-[(2S,6R)-6-[[(S)- role in the management of hypertension; they are effective 1-(ethoxycarbonyl)-3-phenylpropyl] amino]-5-oxo-2-(2- and well-tolerated and offer certain advantages in some thienyl)-1,4-thiazepan-4-yl] acetic acid monohydrochloride, subgroups of patients such as diabetic hypertensives. A large a recently developed carboxyl-containing ACE inhibitor number of ACE inhibitors are now available, the great with a dual excretion pathway. It is the ester prodrug of the majority of which are eliminated predominantly through pharmacologically active diacid metabolite temocaprilat. the kidneys [1, 2]. As a result, elimination is affected by Dose linearity was demonstrated for temocaprilat over the renal impairment in a predictable manner and reductions of dose range of 5–40 mg once daily [Sankyo, data on file]. In doses of ACE inhibitors are generally recommended in this study, we investigated the pharmacokinetics of temocap- patients with reduced renal function [1, 2]. However, some ril and temocaprilat after 14 once daily oral doses of 10 mg of the more recent ACE inhibitors, such as fosinopril and temocapril hydrochloride in hypertensive Caucasian patients spirapril, have dual elimination pathways, both renal and with normal and impaired renal function. The dose studied, hepatic, and when one route of elimination is impaired 10 mg, was selected as it is an effective dose with respect to there is a compensatory increase in the fractional excretion blood pressure reduction but it is at the lower end of the therapeutic range in Caucasians [Sankyo, data on file]. It

Correspondence: Dr Bernd Sierakowski, Sankyo Europe GmbH, Immermannstrasse was expected to be safe and to produce reliable and 45, D-40210 Duesseldorf, Germany. measurable plasma concentrations.

Methods Sample collection and assays On days 5, 8, 11, 12, 13 and 14 predose, blood samples were Patient selection and treatment taken for trough measurements. After the last dose on day Four centres participated, three of which were in Germany 14,bloodsamplesweretakenat0.5,1,1.5,2,3,4,6,8,12, (patients recruited: n=30) and the fourth in the 16, 24, 36, 48, 72, 96 and 120 h. Total urine output was Netherlands (n=2). All subjects provided written informed collected from 0 to 120 h. Blood was drawn into heparinised consent and the study was conducted in accordance with tubes and subjected to centrifugation at 1600 g at 4° Cfor the German Medicines Act, the EU Note for Guidance on 10 min. Plasma and urine samples were stored at −20° C Good Clinical Practice, and the Declaration of Helsinki. until analysis. Plasma and urine concentrations of temocapril Ethics committee approval was obtained before study and temocaprilat were determined using capillary gas chroma- commencement. tography-negative ion chemical ionization mass spectrometry Adult Caucasian subjects with mild to moderate essential (GC-MS) [5]. A deuterated analogue was used as internal hypertension (diastolic blood pressure between 95 and standard and all three compounds were extracted from plasma 114 mmHg, systolic blood pressure 220 mmHg or lower) and urine using a two-stage solid phase procedure with Sep- who had been treated with an ACE inhibitor other than Pak C18 and Sep-Pak silica cartridges. Sequential derivatization fosinopril for at least 3 months were eligible. The degree of carboxylic acid and secondary amino groups was carried of renal impairment was based upon creatinine clearance out using diazomethane and trifluoroacetic acid anhydride, (CLCR) which was assessed by 24 h urine collection on 2 respectively. Negative ion chemical ionization of the deriva- consecutive days during a 3-week screening interval. The tives using methane as reagent gas produced intense high result of the first measurement was set at 100%. The mass fragments ideal for selected ion monitoring. The second had to be in the range 80–120%. If not, a third combination of capillary gas chromatography, derivatization assessment had to be performed which, setting the and monitoring of specific high mass negative ions ensured second at 100%, had to be within the range of 80–120%. no interference from coextracted endogenous plasma compo- The mean of the two relevant results was taken. The nents. Imprecision of the assay did not exceed 3.3% and subjects were grouped according to their CLCR values 11.8% following analysis of CS-622 (temocapril) and as follows: RNH-5139 (temocaprilat) in plasma (8.8% and 3.6%, ≥ −1 Group A CLCR 60 ml min respectively, in urine). Inaccuracy for both analytes did not −1 − + − + Group B CLCR 40–59 ml min exceed 9.8% to 3.9% in plasma ( 9.5% to 12.1% in −1 Group C CLCR 20–39 ml min urine). The lower limit of quantification (LLQ) was < −1 −1 Group D CLCR 20 ml min 0.50 ng ml for both analytes in plasma and urine. Subjects with clinically relevant heart failure, coronary artery disease, valvular defects ( particularly those impeding cardiac Pharmacokinetic evaluation and statistical analysis outflow), renal artery stenosis, only one intact kidney, chronic haemodialysis or any renal condition that might Pharmacokinetic data were analysed by noncompartmental have affected safety were excluded from the study. Subjects techniques using the TopFit 2.1 software. For peak concen- with clinically significant intercurrent medical conditions tration in plasma, Cmax, and time to reach peak concentration, which might have interfered with the evaluation of tmax, observed values were taken. The apparent terminal pharmacokinetics were also ineligible. elimination rate constant, lZ, was determined by linear All subjects had their ACE inhibitors withdrawn 1 day regression of the terminal phase of the log plasma concen- prior to the start of dosing. Subjects with normal renal tration vs time curve. The terminal half-life, tD,Z,was function were allowed to take between one and three calculated as (ln 2)/lZ. Area under the plasma concentration additional antihypertensive drugs including diuretics (e.g. vs time curve was calculated by the linear-logarithmic frusemide, calcium-antagonists, and vasodilative drugs such trapezoidal rule up to 24 and 120 h for AUCSS and as clonidine or dihydrallazine), oral contraceptives, paraceta- AUC(0,120 h), respectively, and, for AUC, up to the last mol or aspirin and, if necessary, the previously used ACE time at which the concentration was equal to or above the inhibitor after the 48 h postadministration sample. Those LLQ, AUC(0,t), and extrapolated to infinity by dividing the with impaired renal function were allowed to take drugs as plasma concentration at time t by lZ and adding this value to above plus insulin, calcium carbonate, cholecalciferol, and AUC(0,t). The apparent total plasma clearance, CL/F,was vitamin preparations. calculated by dividing the dose (10 mg) by the AUCSS for Subjects took temocapril hydrochloride (film-coated temocapril. The renal clearance from plasma, CLR,was tablets supplied by Sankyo Pharma GmbH, Munich, calculated by dividing urinary recovery of temocapril, Ae, Germany) orally at a dose of 10 mg once daily for 14 days. and temocaprilat, Ae(m), by the related AUC(0,120 h). Medication was taken with 200 ml water after a continental The temocapril and temocaprilat trough plasma concen- breakfast between 07.00 h and 09.00 h for the first 13 days trations of days 5, 8, 11, 12 and 13 were analysed by and, after fasting overnight for at least 10 h, on day 14 (last regression analysis. Steady state was characterized by a slope dosing day). On day 14, subjects had a light lunch at 4 h not significantly different to zero. postdose and then a cooked meal at 8 h postdose. At SAS version 6.08 was used for statistical analysis. 12 h they had a light snack. Normal dietary intake resumed Pharmacokinetic parameters (with the exception of tmax) were 24 h after dosing. Blood pressure and pulse rate were analysed using analysis of variance (ANOVA) techniques with taken daily. type of impairment as a factor in the ANOVA model. The

532 © 1997 Blackwell Science Ltd Br J Clin Pharmacol, 44, 531–536 Pharmacokinetics of temocapril in renal impairment renally impaired groups were then compared, if appropriate, Mean (s.d.) plasma concentration vs time curves of with the normal subjects using the Dunnett test as a multiple temocapril after 14 once daily oral doses of 10 mg temocapril comparison procedure. For applicability of the ANOVA, the hydrochloride for all four groups are shown in Figure 1a. equality of variances of the groups was tested using the Bartlett The corresponding pharmacokinetic parameters for temocapril test at a significance level of 10%. In the case of unequal are given in Table 2. There was neither any statistically ff variances, a logarithmic transformation of the parameter was significant di erence in median tmax or mean Cmax,AUCSS, performed, namely the AUC data for temocapril and temocapri- tD,Z,CL/F for temocapril between the four groups nor any ffi lat. The Spearman rank correlation coe cient was calculated significant correlation of these parameters with CLCR.Renal between creatinine clearance on day 14 and each pharmaco- clearance, CLR, for temocapril showed a linear decreasing kinetic parameter. tmax was compared between groups using trend with decreasing CLCR (Figure 2a) and correlated = = the Kruskal–Wallis test and individual pairs of groups compared significantly with CLCR on day 14 (r 0.68, P 0.0001). using the Wilcoxon rank sum test. The groups differed overall (ANOVA, P=0.0001) and Group Adverse events were coded according to the WHO- A was significantly differentfromGroupsB,C,andDin Adverse Reaction Terminology, Version 3.0. pairwise comparisons (Dunett’s test, P<0.05). Temocapril had disappeared from plasma within 8 h of the final dose. Mean (s.d.) plasma concentration vs time curves of Results temocaprilat after 14 once daily oral doses of 10 mg temocapril Thirty-two subjects participated in the study (Table 1). All hydrochloride, i.e. at steady state, for all four groups are subjects in Group A had hypertension while those in Groups shown in Figure 1b. The corresponding pharmacokinetic B–D had renal impairment and hypertension. Creatinine parameters for temocaprilat are given in Table 3. No ff clearance, CLCR, was compared between screening and day statistically significant di erences in mean Cmax or median 14. There was no clinically relevant change in any individual tmax for temocaprilat were detected. With decreasing mean subjects in Group D. In Group C, CLCR decreased in one CLCR,meanAUCSS for temocaprilat increased statistically −1 (38.5–15 ml min ) and increased in two subjects. In three significantly although only two- to threefold and tD,Z was subjects of Group B, CLCR increased, whereas, in one prolonged. However, prolongation of mean tD,Z and increase subject of Group A, there was a substantial decrease in in mean AUCSS did not parallel the decrease of mean renal −1 CLCR from 66 to 31 ml min . clearance for temocaprilat. Median tmax,meanCmax and Temocapril itself was not detected in trough samples. mean tD,Z for temocaprilat did not correlate significantly with Temocaprilat was detectable in trough samples from all but CLCR.CLR for temocaprilat showed a linear decreasing trend one subject from day 5 onwards. The temocaprilat trough with increasing renal impairment (Figure 2b) and correlated = = plasma concentrations of days 5, 8, 11, 12 and 13 were significantly with CLCR on day 14 (r 0.81, P 0.0001). analysed by regression analysis. Steady state was demonstrated The groups differed overall (ANOVA, P=0.0001) and Group by a slope not significantly different to zero, i.e. steady-state A was significantly differentfromGroupsB,C,andDin plasma concentrations were reached from day 5 onwards. pairwise comparisons (Dunett’s test, P<0.05).

Table 1 Patient characteristics. Group A Group B Group C Group D (n=8) (n=8) (n=8) (n=8)

Sex: Males/females 8/0 5/3 5/3 8/0 Age (years) Mean 52.4 53.5 55.1 51.4 Range 35–68 19–82 33–72 31–65 Weight (kg) Mean 82.6 72.8 81.3 77.0 Range 71–96 64–90 65–104 52–98 Height (cm) Mean 176.8 172.4 172.8 176.5 Range 168–186 164–183 156–190 168–186

−1 CL CR (ml min ) [screening] Mean 105.4 50.8 35.9 11.8 s.d. 20.7 6.7 2.8 2.7 Range 66–143 43–60 30–40 9–18 −1 CLCR (ml min ) [day 14] Mean 84.1 57.9 36.4 13.8* s.d. 20.9 13.4 9.9 3.6* Range 31–143 43–79 15–40 9–19*

CLCR Creatinine clearance, average of two assessments on consecutive days during the screening interval and results of one assessment on day 14. *On day 14, by mistake, urine creatinine was not determined in one patient of Group D. Therefore,

only seven patients’ data were used for the CLCR results of Group D on day 14.

a 103

102

101

100 ) –1

10–1 024681357 Time after dosing (h)

b 103 Plasma concentration (ngml 102 Figure 1 Mean (s.d.) plasma concentration vs time curves of (a) temocapril and (b) temocaprilat after 14 101 once daily oral doses of 10 mg temocapril hydrochloride in hypertensive patients with varying degrees of renal impairment. ≥ −1 $ Group A, CLCR 60 ml min ; 100 n=8. −1 # Group B, CLCR 40–59 ml min ; n=8. −1 & Group C, CLCR 20–39 ml min ; –1 n=8. 10 −1 010 20 30 405060 70 80 90 100 110 120 % Group D, CLCR <20 ml min ; Time after dosing (h) n=8

Table 2 Pharmacokinetics of temocapril Group A Group B Group C Group D after 14 once daily oral doses of 10 mg temocapril hydrochloride in hypertensive patients with varying degrees of renal −1 Cmax (ng ml ) 93.2 (47.5) 132.8 (70.0) 203.5 (121.2) 138.7 (66.9) impairment [59.0–127.4] [82.3–183.3] [116.1–290.9] [90.5–187.0] (n=8 in each group). tmax (h) 0.75 (0.5–1.0) 1.00 (0.5–1.0) 0.75 (0.5–1.0) 0.75 (0.5–1.5) −1 AUCSS (ng ml h) 87.3 (34.7) 125.4 (40.8) 193.2 (126.6) 114.1 (57.4) [62.2–112.3] [96.0–154.9] [101.9–284.5] [72.6–155.5] t1/2,Z (h) 1.1 (0.4) 1.0 (0.7) 1.1 (0.3) 1.0 (0.8) [0.8–1.4] [0.5–1.4] [0.8–1.3] [0.4–1.5] − CL/F (ml min 1) 2198 (883) 1468 (508) 1388 (1039) 1739 (709) [1561–2834] [1102–1835] [638–2137] [1228–2250] −1 CLR (ml min ) 32.2 (10.7) 10.2 (5.7) 7.6 (5.2) 3.7 (3.0) [24.4–39.9] [6.1–14.3] [3.8–11.3] [1.5–5.8] Ae (mg) 149.6 (23.1) 73.4 (32.9) 66.9 (56.7) 22.1 (15.4) [133.0–166.3] [49.7–97.1] [26.0–107.7] [11.0–33.2]

Results given as mean (s.d.) and [95% conﬁdence interval] with the exception of tmax which is shown as median (range). = AUCSS Area under plasma concentration-time curve during the dosing interval (t 24 h) after 14 once daily oral doses of 10 mg temocapril hydrochloride; Ae Amount of temocapril recovered in urine (collected from 0 to 120 h after the last dose).

a 50

Figure 2 Linear regression of creatinine 10 clearance on day 14 (CLCR) vs renal clearance (CLR) for a) temocapril and b) temocaprilat after 14 once daily oral doses

of 10 mg temocapril hydrochloride in )

–1 0 hypertensive patients with varying degrees 0204010 305060 70 80 90 100 110 of renal impairment. The estimated regression equations (mlmin were: y=−0.009+0.282Ωxandy= R b

− + Ω = CL 30 0.612 0.308 x (with x CLCR and y=CLR) and the limits of its 95% conﬁdence interval are shown. Each data point represents the data of one patient. −1 $ Group A, CLCR ≥60 ml min ; n=8*. −1 20 # Group B, CLCR 40–59 ml min ; n=8. −1 & Group C, CLCR 20–39 ml min ; n=8. −1 % Group D, CLCR <20 ml min ; n=7**. *In one patient of Group A, there was a 10 substantial decrease in CLCR from 66 to − 31 ml min 1 from baseline to day 14. **On day 14, by mistake, urine creatinine was not determined in one patient of Group D. Therefore, only seven patients’ data were used for the CLCR results of 0 Group D on day 14 and subsequently for 0204010 305060 70 80 90 100 110 –1 linear regression analysis. CLCR (mlmin )

The majority of adverse events recorded were mild in showed in Japanese patients that mean AUC(0, 48 h) for severity with others being moderate. One subject in Group temocaprilat (after a single dose of 1 mg temocapril) was D was withdrawn at day 15 due to impaired renal function. increased only twofold (relative to normal controls) in those < −1 He underwent haemodialysis without any sequelae. with a CLCR of 30 ml min whereas mean AUC(0, 48 h) for enalaprilat (after a single dose of 5 mg enalapril) increased thirteenfold. Mean C of enalaprilat increased with renal Discussion max impairment but that for temocaprilat did not. After a single The impact of renal function on the pharmacokinetics of dose of 2.5 mg temocapril, again in Japanese subjects, similar temocapril and temocaprilat was primarily demonstrated by results to those with a 1 mg dose were obtained for an approximately twofold increase of the mean AUCSS for temocaprilat. Cmax, AUC and tD,Z for temocaprilat were ﬀ < temocaprilat with progressive impairment and a statistically only slightly di erent in subjects with CLCR of 30, > −1 signiﬁcant linear relationship between mean CLR and CLCR 30–70, and 70 ml min . AUC was higher in those with −1 for temocapril as well as for temocaprilat. However, the lowest CLCR (977 compared with 565 ng ml h) [7]. prolongation of the mean tD,Z and increase of mean AUCSS Biliary excretion of temocapril has been demonstrated in for temocaprilat did not parallel the approximately sixfold humans [8]. Furthermore in another study, a single oral decrease of mean CLR and CLCR. dose of 20 mg temocapril hydrochloride was administered The results obtained in this study in Caucasian subjects to 12 patients undergoing endoscopic retrograde cholangio- support and extend those of Oguchi and colleagues [6] who pancreatoscopy. Temocapril and its temocaprilat were

Table 3 Pharmacokinetics of Group A Group B Group C Group D temocaprilat after 14 once daily oral doses of 10 mg temocapril hydrochloride −1 Cmax (ng ml ) 455 (77.3) 594 (95.2) 593 (118.0) 474 (146.9) in hypertensive patients with varying [399–511] [526–663] [508–678] [368–580] degrees of renal impairment (n=8in tmax (h) 1.50 (1.0–2.0) 1.75 (1.5–2.0) 1.50 (1.0–2.0) 1.50 (1.0–2.0) each group). −1 AUCSS (ng ml h) 2115 (565) 4773 (1043) 4989 (2338) 3744 (1438) [1707–2522] [4021–5525] [3303–6675] [2707–4781] AUC(0,120 h) 2406 (585) 5959 (1486) 6477 (3707) 4506 (1576) − (ng ml 1 h) [1984–2828] [4887–7031] [3804–9150] [3369–5642] − AUC (ng ml 1 h) 2410 (587) 5982 (1482) 6538 (3784) 4583 (1539) [1987–2833] [4914–7051] [3809–9267] [3473–5692] t1/2,Z (h) 15.2 (1.2) 17.6 (4.4) 20.0 (2.4) 20.0 (7.5) [14.4–16.1] [14.4–20.8] [18.2–21.7] [14.5–25.4] −1 CLR (ml min ) 20.2 (4.3) 7.8 (3.5) 6.6 (2.1) 3.0 (1.8) [17.1–23.3] [5.3–10.3] [5.0,–8.1] [1.7–4.3] Ae(m) (mg) 2953 (879) 2621 (977) 2318 (834) 823 (548) [2320–3587] [1917–3325] [1717–2919] [428–1218]

Results given as mean (s.d.) and [95% confidence interval] with the exception of tmax which is shown as median (range). detected in bile sampled directly from the common bile 2 Leonetti G, Cuspid C. Choosing the right ACE inhibitor—a duct. Thus, there was evidence for a dual route of excretion guide to selection. Drugs 1995; 49: 516–535. for both temocapril and its temocaprilat [Sankyo, data on 3 Murdoch D, McTavish D. Fosinopril—a review of its file]. It is possible that the relative lack of accumulation in pharmacodynamic and pharmacokinetic properties, and renally impaired subjects is a reflection of this dual therapeutic potential in essential hypertension. Drugs 1992; 43: 123–140. elimination, a reduction in one pathway being compensated 4 Stein G, Sierakowski B, Grass P, Haufe CC, Jansa U, by an increase in the other. Such a shift in elimination had Weidinger G. Pharmacokinetics of spirapril and spiraprilat in been described for fosinopril [9]. A minimal degree of patients with chronic renal failure. Blood Press 1994; 3(Suppl accumulation is seen upon multiple dosing of fosinopril in 2): 47–53. −1 subjects with CLCR <30 ml min [10]. 5 Shioya H, Shimojo M, Kawahara Y. Determination of a new Recently, it was shown that the ATP-dependent canalicu- angiotensin-converting enzyme inhibitor (CS-622) and its lar multispecific organic anion transporter is responsible for active metabolite in plasma and urine by gas chromatography- the biliary excretion of temocaprilat in rats [11]. mass spectrometry using negative ion chemical ionization. Furthermore, in vitro studies using rat bile canalicular J Chromatogr 1989; 496: 129–135. membrane vesicles demonstrated similar results [11]. 6 Oguchi H, Miyasaka M, Koiwai T, et al. Pharmacokinetics of temocapril and enalapril in patients with various degrees of There was a small, clinically not relevant, increase in the renal insufficiency. Clin Pharmacokin 1993; 24: 421–427. frequency of adverse events in subjects with renal impair- 7 Nakashima M, Yamamoto J, Shibata M, et al. ment. Six subjects each in Groups B and D had adverse Pharmacokinetics of temocapril hydrochloride, a novel events compared with five subjects in Group A. An increased angiotensin converting enzyme inhibitor, in renal frequency of cough in patients with renal failure has been insufficiency. Eur J Clin Pharmacol 1992; 43: 657–659. reported during treatment with ACE inhibitors [12], but 8 Suzuki H, Kawaratani T, Shioya H, Uji Y, Saruta T. Study not following temocapril in this study. This is probably on pharmacokinetics of a new biliary excreted oral related to excessive drug accumulation in such subjects and angiotensin converting enzyme inhibitor, temocapril (CS-622) thus dependent upon the actual ACE inhibitor used. in humans. Biopharm Drug Dispos 1993; 14: 41–50. In conclusion, it may be assumed that temocaprilat is 9 Singhvi SM, Duchin KL, Morrison RA, Willard DA, Everett DW, Frantz M. Disposition of fosinopril sodium in healthy substantially excreted via the bile, possibly in a dose- subjects. Br J Clin Pharmacol 1988; 25: 9–15. dependent manner. This would be an alternative excretion 10 Sica DA, Cutler RE, Parmer RJ, Ford NF. Comparison of pathway of particular importance in renally impaired patients. the steady-state pharmacokinetics of fosinopril, lisinopril and Nonetheless, to circumvent any potential risk, a reduced enalapril in patients with chronic renal insufficiency. Clin dose of temocapril hydrochloride may be appropriate in Pharmacokin 1991; 20: 420–427. patients with moderate to severe renal impairment. 11 Ishizuka H, Konno K, Naganuma H, et al. Temocaprilat, a novel angiotensin converting enzyme inhibitor, is excreted This study was supported by a grant of Sankyo Europe into bile via an ATP-dependent active transporter (cMOAT) GmbH. that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR). J Pharmacol Exp Ther 1997; 280: 1304–1311. 12 Sorooshian M, Eynon CA, Webb DJ, Eastwood JB. Cough References associated with ACE inhibitors: increased frequency in renal failure. Eur J Intern Med 1991; 2: 15–17. 1 Kelly JG, O’Malley K. Clinical pharmacokinetics of the newer ACE inhibitors—a review. Clin Pharmacokinet 1990; (Received 13 March 1997, 19: 177–196. accepted 27 July 1997)