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 *1 興 和 株 式 会 社 東 京 研 究 所 〒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 tration of 6 mg NIP to 6 human sub and dose in each human subject. ○: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(★).