臨床 薬 理 16巻4号 1985年12月 679

Pharmacokinetics of Nipradilol (K-351), a New Antihypertensive Agent, in Human

Mitsuo YOSHIMURA*1 Junji KOJIMA*1 Terufumi ITO*1 Junnosuke SUZUKI*1 Sueharu TSUTSUI*2 and Kazuzo KATO*3

(Received on July 9, 1985)

*1 Tokyo Research Laboratories, Kowa Co., Ltd., Noguchi-cho, Higashimurayama, Tokyo 189, Japan *2 Laboratory of Psychosomatic Medicine , Toho University School of Medicine *3 The Cardiovascular Institute Hospital

The Pharmacokinetics of nipradilol (K-351 : 3, 4-dihydro-8-(2-hydroxy-3-iso propylamino) propoxy-3-nitroxy-2H-1-benzopyran ; NIP), a new potent antihyperten sive and antianginal agent, were investigated in healthy volunteers after single or repeated oral administration. After administration at single doses of 1 mg to 24 mg, NIP was rapidly absorbed, reaching a maximum plasma concentration (Cmax) at 2 hr, and then eliminated with a plasma half-life ( T1/2) of 3.7 hr, irrespective of the dose. Cmaxand area under the plasma levels-time curve (AUC) of NIP, as well as the amounts of NIP and its metabolites excreted in the urine increased in proportion to the dose administered. The apparent volume of distribution, systemic availability, renal clearance, and plasma clearance were 5.621/kg,35%, 0.181/min, and 1.041/min, respectively, independent of the dose. Upon multiple oral administration of 6 mg two times daily for one or seven days, the experimental plasma concentrations of NIP and denitrated NIP coincided well with the

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〒189 東 京 都 東 村 山 市 野 口 町2-17-43 *2 東 邦 大 学 医 学 部 心 療 内 科 *3 心 臓 血 管 研 究 所 付 属 病 院 680

simulation curves. Furthermore, T1/2 values calculated from the plasma and urinary excretion rate did not differ significantly during repeated dosing, indicating no accumulation in the body. The amount of parent drug excreted into the urine was 6.3%. The major urinary metabolites arose from three metabolic pathways, namely, denitration, hydroxylation of the ring system and glucuronidation of NIP. Degradation of the isopropylaminopro panol side chain was a minor route. Key words : nipradilol (K-351), antihypertensive agent, pharmacokinetics, meta bolism, healthy volunteer

and multiple oral administration. Introduction

Materials and Methods Nipradilol (K-351 : 3, 4-dihydro-8 ( 2-hy droxy-3-isopropylamino) propoxy-3-nitroxy 1. Drug 2H-1-benzopyran ; NIP) is -a new type of potent NIP tablets (Kowa Co.,Ltd.) containing 1 mg antihypertensive and antianginal agents synthe or 3 mg of the active ingredient were used. sized in our laboratories. NIP has an isopropyl 2. Subjects aminopropanol side chain and a nitroester group The subjects were 11 healthy adult males aged as active functions in the molecule, and its from 21 to 37 years and weighted from 53.5 to 80 pharmacological profile is nonselective beta kg who were allocated 6 and 5 males per group for adrenoceptor blocking and vasodilating action single and multiple oral studies, respectively. not only on arterial but also on venous vessels1)2). 3. Oral administration

In the spontaneously hypertensive rats and de Single oral dose : The respective doses of 1 oxycorticosterone acetate/saline hypertensive mg, 3mg (1•~3mg tablet), 6mg(2•~3mg rats, NIP showed a long-lasting antihypertensive tablet), 9mg(3•~3mg tablet), 12mg(4•~3mg action after a single oral administration2).NIP tablet),18mg (6•~3mg tablet), and 24mg(8•~3 was found to be a very safe drug with no serious mg tablet), were taken together with 150 ml of side effects by various toxicity studies in water at 1.5 hr after a light meal (at the doses of animals. 1 mg to 9mg) or ordinary meal (at more than 12

The previous work3)4)5)has shown that in dogs, mg). More than one week intervened between monkeys, rabbits, and rats, NIP was completely doses. Blood samples were taken before and at absorbed and extensively distributed to the tis the following times after administration : 0.5, 1, sues, but underwent extensive first-Pass metab 2, 3, 4, 6, 8, and 22hr. Urine was collected during olism due to the denitration. the periods 0-2, 2-4, 4-6, 6-8, 8-12, and 12-24 hr

In the present study, for the purpose of eluci after administration. dating the absorption, distribution, metabolism, Multiple oral dose : (1) Two times daily for one and excretion of NIP in healthy volunteers, the day ; 5 subjects took two tablets containing 3mg pharmacokinetics of NIP were investigated in a of NIP at 9 : 00 and 18:00 after ordinary meal. phase one study which was performed by single Blood samples were obtained before and at the 681 following times after the first administration: 1, Tab.1 Summary of Abbreviations , 2, 3, 8, 10, 11, 12, 23, 31, and 45 hr. Urine was Definitions and Equations collected during the periods 0-2, 2-4, 4-6, 6-9, 9-11, 11-13, 13-27, 27-32, and 32-45 hr. (2)Two times daily for 7 days; 5 subjects took tablets as in the above protocol for 6 days, and then only at 9 : 00 on the 7th day. Blood samples were taken at 2, 3, 8, and 23 hr after the first administration on the 1st, 3rd, and 5th days, and at 1, 2, 3, 4, 6, 8, 12, and 23 hr on the 7th day. Urine was collected during the periods 0-2, 2-4, 4-6, 6-9, 9-12, and 12-24 hr on the 1st and 7th days, and 0-9 and 9-24 hr on the 2nd day to 6th day. 4. Analytical methods NIP and denitrated NIP (DNIP), one of the major metabolites, in plasma were determined by a selected ion monitoring method (SIM) using GC-MS after derivatization into the acyl com pounds with heptafluoro-n-butyric anhydride and trimethylamine, as previously reported4). NIP and its various metabolites in urine were sepa Results rated into basic and acidic fractions and were 1. Single oral administration determined by SIM after derivatization into the 1-1. Plasma levels above acyl compound and methylestertrimethyl The mean plasma levels of NIP after single silyl ether, respectively3). Metabolites conjugated oral administration at the dose of 1 mg (n=6), 3 with glucuronic acid in plasma and urine were mg (n=6), 6mg (n=6),9mg (n=4),12mg (n determined as the difference between the concen =3) , 18mg (n=3), and 24mg (n=3) are trations of metabolites before and after enzymatic shown in Fig.1, and pharmacokinetic parameters hydrolysis, as previously reportee. are summarized in Tab.2. 5. Pharmacokinetic analysis The plasma levels of NIP reached a peak at 2 Pharmacokinetic parameters were calculated hr, and then declined linearly in the semilogarith as defined in Tab. 1. The simulation curve on mic plot. The biological half-life (Ti/2) was multiple dosing was calculated by a biexponen about 3.7 hr and did not differ significantly with tial model of Lowenthal et al8)., using the para the dose. The maximum plasma concentration meters at the initial dosing. Values are expressed (C.) of parent drug varied as a linear function as mean and standard errors. of the dose (Tab.2). A graph of area under the plasma levels-time curve (AUC) vs dose for each subject is provided in Fig.2. The rela tionship between AUC and oral dose was linear, and the straight line was extrapolated near the 682

origin. There was less than a 2-fold difference in Cmax or AUC obtained in different subjects. The fraction (F) of the dose available for systemic circulation, calculated on the base of the equation (Tab.1), was 35.1% (range 31.5-41.6%) of the administered dose, irrespective of the dose. Therefore, the first-pass metabolism was esti mated to be 64.9%. Plasma clearance (Clp) and the apparent volume of distribution ( Vd) were 1.04 1/min and 5.62 1/kg, respectively ( Tab.2). Upon oral administration to subjects, DNIP, NIP glucuronide and DNIP glucuronide as major metabolites were detected in the plasma(Fig.3), reached a peak at about 2.2, 2.4, and 3.2 hr, Fig.1 Mean plasma levels of NIP after respectively, and were eliminated with T1/2 of oral administration to human sub about 7.9, 2.7, and 4.8 hr, respectively, not jects at the dose of 1mg(○),3mg depending upon the dose. Cmaxand AUC of their (●),6mg(△),9mg(▲),12mg (□),18mg(■)and24mg(★). metabolites were proportional to the dose given,

Tab.2 Pharmacokinetic Parameters after Single Oral Administration in Human Subjects

Values are the mean•}standard error. 683 similar to those of the parent drug. mg are shown in Fig.4. The urinary excretion of 1-2. Urinary excretion NIP occurred rapidly during the first 12 hr and The time course of the mean cumulative uri was almost complete within 24 hr. The amount of nary excretion for NIP in the dose from 1 mg to 24 NIP excreted in urine was estimated to be 6.3%,

Fig.3 Mean plasma levels of NIP and its Fig.2 Relationship between AUC of NIP metabolites after single oral adminis and dose in each human subject. tration of 6 mg NIP to 6 human sub

○:subject 1, ●:subject 2, △:subject 3, jects. ○:NIP, △:Free+Conjugated NIP, ▲:subject 4, □:sublect 5 , ■:subiect 6 ●:DNIP, ▲:Free+Conjugated DNIP

Fig.4 Mean cumulative urinary excretion and log sigma-minus plot of urinary ex creted NIP after single oral administration at the dose of 1mg (○), 3mg(●), 6 mg(△), 9mg(▲)12mg(□), 18mg(■)and 24mg(★). 684 not depending upon the dose. The time course of the urinary excretion rate was similar to that of the plasma level.The maximum urinary excretion rate appeared at 2.4 hr after administration, the value being in agree ment with the plasma Tmax T1/2 of urinary excretion estimated from sigma-minus plot was 3.4 hr, and did not differ significantly with the dose (Fig.4), as with the plasma T1/2.A graph of the AUC versus the drug accumulation in urine (Xu) for each subject is provided in Fig.5. A relationship between Xu and AUC was linear, and the straight line was extrapolated near the Fig. 5 Relationship between urinary excre origin. From the correlation, renal clearance (Clr tion of NIP and AUC in each human =Xu/AUC) was calculated to be 0.18 1/min. subject.

Therefore, nonrenal cleãrance (Chir=Clp-Clr) ○:subject 1,●:subject 2,△:subject 3 , ▲:subject 4 was estimated to be 0.86 1/min, indicating a high ,□:subject 5,■:subject 6 metabolic clearance.

Tab.3 Metabolites in 24-hr Urine of Human Subjects after Single Oral Administra tion of NIP 685

Fig.6 Mean plasma levels of NIP (○)and DNIP(●) in human subjects after oral administration of 6 mg NIP two times daily for one day.

Predicted curves (dotted line) were generated from parameters at first dosing

as follows :

NIP : Cp=6.15 (e-0.191(t-0.69) e-1.546(t-0.69))

DNIP : Cp= 9.34 (0.074(t-0.89) e-3.077(t-0.89)

Values are the mean•}standard error from 5 experiments .

The identification of urinary metabolites was In regard to parent drug, the pharmacokinetic carried out by comparison of the mass spectral parameters (T.:1-2hr, C. : 5 ng/ml, T1/2 : fragmentation with those of samples isolated from 3.8hr) obtained after the first and second dosing dog urine or synthesized3). Tab. 3 lists the mean did not differ significantly, and the time course of quantities of metabolites identified in the 0-24 hr plasma levels after the second dosing was to urinary fraction at the dose of 12mg to 24mg. be similar to those calculated by a biexponential The major metabolites were DNIP (17.4% of model using the parameters at the first dosing dose), 4-hydroxy derivatives (total 11.4%) and (Fig.6). The systemic availability (F) was NIP glucuronide (10.5%). On the other hand, calculated to be 36.4% ,the value being in excel N-deisopropyl metabolites and lactic acid or lent agreement with that of single administration. acetic acid-type metabolites, products of the As for DNIP, Cmaxvalue on the second dosing dealkylation and subsequent oxidative deamina was about 1.4 times higher than that on the first tion of the side chain, were minor metabolites. dosing, on account of longer T1/2, but coincided 5-Hydroxy, N-methyldeisopropyl, and glycol well with the calculated value (Fig.6). type metabolites, which were found in dogs, were The time course of the mean cumulative uri not detected in human. nary excretion of NIP and its metabolites are 2. Multiple oral administration shown in Fig.7. Their urinary excretion almost 2-1. Two times daily for one day completed within 24 hr after the second dosing. The mean plasma levels of NIP and DNIP after The amount of NIP, DNIP, NIP glucuronide , and oral administration of 6 mg of NIP at 9:00 and DNIP glucuronide excreted in urine were esti 18:00 for one day are shown in Fig.6. mated to be 12.3, 24.2, 14.1, and 5.8%, respec 686

tively. each dosing interval) and T1/2. values obtained

2-2. Two times daily for 7 days after the daily first dosing were 2.4 hr (ranging

The time course of NIP concentration in the from 2.4 to 2.6 hr), 4.7 ng/ml(4.3-5.8 ng/ml),

plasma is shown in Fig. 8. The mean Tmax,Cmax, 0.6 ng/ml(0.5-0.7 ng/ml), and 3.2 hr(2.9-3.3

Cmin (the drug concentration at the end of the hr), respectively, and did not differ significantly

during repeated dosing. In addition the ex

perimental plasma concentrations of NIP during

repeated dosing were in good agreement with the

simulation curve based on the data obtained after

the initial dosing (Fig.8).

On the results of the urinary kinetic analysis,

T1/2 of NIP on the 1st and 7 th days were 3.34•}0

.51 and 3.57•}0.22 hr, respectively, indicating

no significant differences during repeated dosing,

similarly on the plasma concentration study

results. The extent of urinary excretion of NIP

for each day was nearly equal (Fig.9), and the

total urinary excretion of NIP amounted to 6.35•}

0.71mg (8.14•}0.91% of dose).

As for DNIP, the Cmax and Cmin values obtained

from the plasma levels after the daily first dosing

increased during the first 3 days, and then

flattened out (Cmax:10.0 ng/ml, Cmin : 5.2

Fig.7 Mean cumulative urinary excretion ng/ml), coinciding with those predicted from the

of NIP and its metabolites after oral initial dosing (Fig.8). The T1/2 values calculat administration of 6 mg NIP two ed from the plasma and urinary excretion data did times daily for one day to 5 subjects. ○:NIP, △:NIP glucuronide, not vary during repeated dosing. The daily

●:DNIP, ▲:DNIP glucuronide, amount of urinary excretion of DNIP (Fig.9) □:Total was gradually increased from on the 1st day (1.73

Fig.8 Mean plasma levels of NIP(○)and DNIP(●) after multiple oral administra tion of 6 mg NIP two times daily on day 1-6 and once daily on day 7. Dotted line represents predicted curve. 687

Fig. 9 Mean urinary excretion of NIP, DNIP, and their glucuronides after multiple oral administration of 6 mg NIP two times daily on day 1-6 and once daily on day 7.

mg) to the 3rd or 4th day (2.30mg), which was ics of NIP did not vary with doses in the range compatible with the plasma conceintration. The from 1mg to 24 mg. total urinary excretion of DNIP amounted to Differing from the above results, in laboratory 14.86 1.07mg (22.1•}1.6% of dose). animals, dose-dependent bioavailability and shorter T1/2 were observed4). However, the appar Discussion ent threshold dose (ATD) which was estimated This paper contains data on the pharmacokinet with the zero-AUC intercept varied inversely ics of NIP, a newly developed antihypertensive with body weight of the animal species, and in agent, in male healthy volunteers after single or humans, linear pharmacokinetics was predicted multiple oral administration. by extraporation of the above animal data to

In the oral dose-ranging pharmacokinetic human4), which was in good agreement with the study, NIP was rapidly absorbed from the gas results of this study. These species differences in trointestinal tract, reaching Cmax at 2 hr after ATD seem to be closely related to the finding that dosing, and then was eliminated with T1/2 of 3.7 the hepatic enzyme activity of denitration9), one hr, not depending upon the dose. Cmax, AUC, and of the major activities in the metabolism of NIP, the amounts of NIP and its metabolites excreted or the microsomal mono-oxygenase10)have been in the urine increased in proportion to the dose observed to vary inversely with body weight of administered, while various pharmacokinetic pa the animal species. rameters with reference to bioavailability, dis Since antihypertensive agents are used in tribution, and clearance remained unchanged. chronic treatment, a linear pharmacokinetic prop

These results suggested that the pharmacokinet erty with no accumulation of drug in the body 688 seems to be of particular necessary for long-term ubility to above parameters is discussed below. efficiency and safety. From the pharmacokinetic In this study, the apparent volume of distribu parameters obtained after single administration, tion (Vd) was calculated to be 5.62 1/kg, which the plasma levels of NIP upon multiple dosing, is 8-fold larger than the total body water in two times daily for 7 days, would be expected to humans, suggesting high affinity in tissues. This show the same daily pattern whereas Cmax and extensive tissue distribution was consistent with Cmin values of DNIP would be predicted to following finding in the rat : unchaged 14C-NIP increase gradually during the first 3 days on showed high affinity in various tissues, especial account of longer T1/2. The experimental plasma ly in kidney, lung, heart and inferior vena cave concentration of NIP and DNIP were in accord which were considered target organs14).However, ance with the respective simulation curves, and there was negligible uptake of NIP into the brain the increase in the T1/2 value with the repetitive because of its less lipophilicity14), indicating the dosage was also not observed. Furthermore, the impossibility of side-effects caused by lipophilic results on the urinary kinetic analysis of NIP and beta-blockers such as propranolol15)which con its metabolites coincided well with the plasma centrate in the central nervous system. Since NIP data. These findings suggested that pharmaco possesses relatively large Vd value among the kinetic properties such as absorption, distribu beta-blockers16)17)despite its lower lipophilicity tion, metabolism and excretion were not changed with its value being the same order of magnitude during multiple dosing, and the normal two times as that of nitrate drugs such as glyceryl daily dosage scheme did not lead to accumulation trinitrate18) and isosorbide dinitrate19)20)in humans, in the body. Also, in dogs chronically treated the nitroester group in NIP is assumed to partly with a high dose (10mg/kg/day) of NIP for 6 contribute to the larger Vd. From the linear months, it has been demonstrated that no accu relationship between Cmaxand the oral dose, Cmax mulation of NIP and DNIP was detected in of NIP corresponded to only 1 ng/ml per dose 1 plasma, so that NIP was found to be a very safe mg (Tab.2).Therefore, these low plasma levels drug with no serious side effects11). seem to be attributable to not only larger Vd but NIP is chemically related to most beta-block also to the first-pass metabolism. ers except nitroester group by the same iso Differing from above assumption according to propylaminopropanol side chain and aromatic lipophilicity, the systemic availability of NIP ring system. It is well known that liposolubility was only 35%, not depending upon the dose, but of the beta-blockers determines their pharmaco its value appears to belong to the middle group kinetic properties : highly liposoluble beta among beta-blockers16)17). In contrast, propra blockers exhibit extensive uptake into the brain, nolol21)has a strong first-pass metabolism which high hepatic extraction ratio, and high protein leads to non-linear pharmacokinetics due to the bindingi2). saturation of drug extraction by the liver. As for The partition coefficient of NIP between n the main pathway of the first-pass metabolism in octanol and pH 7. 4 buffer is 0. 8513),much lower NIP, the rapid appearance and high concentra than that of propranolo112), presuming little affin tion of DNIP and NIP glucuronide in human ity of NIP in the brain, high bioavailability, and plasma (Fig.3) and urine (Tab.3) indicates low protein binding. The contribution of liposol denitration of the nitroester group and glucuro 689 nidation. In dogs, it is already confirmed this Following single oral administration of NIP, first-pass metabolism occurs in the liver and/or 6.3% of the dose was excreted into human urine intestinal tract5). Furthermore, denitration of NIP in the form of parent drug, thus suggesting was catalyzed by GSH-dependent organic nitrate extensive metabolism. Each of the metabolites reductase similarly to glyceryl trinitrate and found in human were also detected in all tested isosorbide dinitrate, but its enzymatic reaction animal species3)4)5). A summary of the proposed rate in rat liver was extremely slow as compared metabolic pathways of NIP in humans are shown with the above nitrate drugs9). T1/2 and the Fig. 10. bioavailability of NIP observed in the present The major urinary metabolites arose from three study were longer and higher, respectively, than metabolic pathways, namely, denitration, hy- those of the above conventional coronary droxylation of the ring system, and glucuronida- vasodilators18)19)20),reflecting the difference in tion. The total amount of the metabolites possess- vitro. ing the isopropylaminopropanol side chain was High protein binding, which was demonstrated estimated to be 52.0 % of the dose, and degrada- in the highly liposoluble beta-blockers, may tion of the side chain, which included dealkyla- bring on variation in the plasma concentration of tion and oxidative deamination, was a minor unbound drug, which is an unfavorable factor as a route. In human, hydroxylation of the ring system predictable effect. As expected, the less liposolu- gave only 4-hydroxy metabolites but not a ble NIP was bound but little to human serum 5-hydroxy isomer, showing pronounced species albumin (11%), a1-acid glycoprotein (26%), difference. That is to say, all animal species and human plasma protein (34%)13) as compared except monkeys formed both 4- and 5-monohy- with propranolol (55%, 69% and 93%, respec- droxylated isomers whereas monkeys excreted tively)22). mainly the former4). It is considered that both

Fig. 10 Possible metabolic pathways of NIP in human. R=ONO2 or OH 690 isomers differ in not only in position on the ring Pharmacobio-Dyn., 8 : 738-750 (1985). system but also in the following metabolic 5) Yoshimura, M., Kojima, J., Ito, T. et al.: Pharmacokinetics of Nipradilol (K-351), a mechanism : 4-hydroxy isomer is directly pro- new antihypertensive agent II. Influence of the duced by stereoselectively aliphatic hydroxyla- route of administration on bioavailability in tion, giving trans-conformation with 3- and dogs. J. Pharmacobio-Dyn., 8 : 503-512(1985). 4-substituents in pseudoaxial position3) while 6) Giudicelli, J. F., Chauvin, M., Thuillez, C. et al.: β-Adrenoceptor blocking effects and aromatic hydroxylation in the 5-position may pharmacokinetics of betaxolol (SL 75212) in occur by an arene oxide-NIH shift process. man. Br. J. clin. Pharmac., 10 : 41-49 (1980). Accordingly, lack of aromatic hydroxylation in 7) Kabuto, S., Kimata, H., Yonemitsu, M. et al.: humans and monkeys is of particular interest in Pharmacokinetics of nipradilol (K-351), a new antihypertensive agent in rats. I. Metabol- respect of the above metabolic mechanism. ism and disposition after single oral adminis- In conclusion, the pharmacokinetic profile of tration of 14C-nipradilol. Arzneim.-Forsch./ NIP is rapid absorption, a good linearity between Drug Rev., 35 : 1674-1679 (1985). Cmax or AUC and the dose, moderate T1/2 and 8) Lowenthal, W. and Vitshy, B. L. : Computer program for a double exponential equation to bioavailability, no accumulation by multiple determine biological constants. J. Pharm. Sci., administration, small intersubject variation in 56 : 169-173 (1967). plasma level, large distribution volume without 9) Kabuto, S., Kimata, H., Yonemitsu, M. et al.: Metabolism of nipradilol (K-351) by liver penetration to the brain, and low protein binding. homogenates from different species. I. Compa- It can be considered that NIP possess the rative studies on the denitration of nipradilol pharmacokinetic properties of both moderately and other organic nitrates. Xenobiotica, sub- liposoluble beta-blockers and nitrate drugs, mitted for publication. which are chemically related to NIP. 10) Walker, C. H. : Species differences in micro- somal mono-oxygenase activity and their rela- tionship to biological half-lives. Drug Metab. References Rev., 2 : 295-323 (1978). 11) Tsuruta, T., Kato, Y., Okubo, M. et al.: 1) Uchida, Y. : Cardiovascular effect of 3, 4-dihy- Twenty six week oral toxicity study of Nipradi- dro-8-(2-hydroxy-3-isopropylaminopropoxy) lol (K-351) in dogs. Oyo Yakuri-Pharma- -3-nitrato-2H-1-benzopyran (K-351) . Jpn. cometrics, 29 : 1005-1022 (1985). (in Japanese) Heart J., 23 : 981-988 (1982). 12) Woods, P. B. and Robinson, M. L.: An inves- 2) Uchida, Y., Nakamura, M., Shimizu, S. et al.: tigation of the comparativ liposolubilities of Vasoactive and β-adrenoceptor blocking prop- erties of 3, 4-dihydro-8-(2-hydroxy-3-isopro- β-adrenoceptor blocking agents. J. Pharm. Pharmacol., 33 : 172-173 (1981). pylamino) propoxy-3-nitroxy-2H-1-benzo- 13) Yoneda, M., Ohkawa, Y. and Muramatsu, T.: pyran (K-351), a new antihypertensive agent. Physico-chemical properties and stabilities of Arch in Pharmacodyn. Ther., 262 : 132-149 nipradilol (K-351). Iyakuhin Kenkyu, 16 : (1983). 1100-1111 (1985).(in Japanese) 3) Yoshimura, M., Kojima, J., Ito, T. et al.: 14) Kimata, H., Kabuto, S., Yonemitsu, M. et al.: Structural determination of dog and human Pharmacokinetics of nipradilol (K-351), a urinary metabolites of Nipradilol (K-351), a new antihypertensive agent in rats. II. A single new antihypertensive agent. Chem. Pharm. oral administration of 14C-nipradilol to spon- Bull., 33 : 3456-3468 (1985). taneously hypertensive rats (SHR). Arzneim- 4) Yoshimura, M., Kojima, J., Ito, T. et al.: Forsch./Drug Rev., 35 : 1680-1684 (1985). Pharmacokinetics of Nipradilol (K-351), a 15) Myers, M. G., Lewis, P. J., Reid, J. L. et al.: new antihypertensive agent I. Studies on in- Brain concentration of propranolol in relation terspecies variation in laboratory animals. J. 691

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