CHEMOTHERAPY 16 JAN. 19987 PHARMACOKINETIC STUDIES OF CEFOPERAZONE AFTER BOLUS INJECTION IN PATIENTS WITH BENIGN PROSTATIC HYPERTROPHY SYUJIFUKUSHIMA, TAKESHI MIURAand TOSHIMICHI SUGAWARA Department of Urology, YokohamaMunicipalCitizens Hospital IICHIRO KONGO and HIROSHIFUJII Department of Urology, KanagawaPrefectural HospitalCenter for the Adult MAKOTO HIROKAWA and AKIRAIWASAKI Department of Urology, Fujisawa MunicipalHospital EIICHIISHIEUKA and NAOTOKITAHMA Department of Urology, YokohamaRed Cross Hospital (ReceivedSeptember 2, 1985) We measured intravenous and to 53 concentrations (T1/ 2ƒÀ) was who and after administration. tained left patient In In patients maximum of with cefoperazone benign sustained groups, the According into detected maximum the in prostatic serum. (CPZ) following its hyperplasia. The 39.8 ƒÊg/ to our CPZ in urine of findings may after and the drug's biological transurethral g at CPZ 2.3 in effective operation INTRODUCTION In general, an antibiotic is administered according to its antimicrobial spectrum and ability to penetrate the affected organ. Recently, there have been many reports concerning the penetration of various antibiotics into specific tissues. ADACHI1), SAKURAI2),and RISTUCCIA3)measured the concentrations of several antibiotics in the prostates of patients with benign prostatic hypertrophy (BPH). We previously reported that in the presence of BPH cefoperazone(CPZ) appears in high concentration in prostatic tissue and suggested that this agent is suitable for the treatment of bacterial prostatitis4). In the study reported here, we performed a pharmacokinetic evaluation of CPZ's penetrability into prostate. g, half-life after the declined bacterial In in bacteria prostatic medical Municipal pital ages saline for was thral Blood tration For was 1 g 60 in of 53 patients. dissolved procedures (TUR) or determination drawn determination only of the once serum after intraprostatic 1983. (70.4•}5.7, and in prior retropubic of Hos- March, Kidney injected operative Cross years 1. The Ka- Fujisawa Red 83 all CPZ admitted Hospital, and to in Fig. normal BPH Adult, intravenously resection for 1982 from shown of with the Yokohama January, were BPH. METHODS Citizens for and ranged solution its prostatitis males Center as functions A 53 Hospital, mean•}SD), that and cause Municipal between Their with capacity AND were nagawa three hyperplasia. subjects Yokohama g at- all parallel that PATIENTS The to the the min 34.3 ƒÊg/ concentration inhibitory the benign the in at 8.6 was administration. prostate its of CPZ respectively, concentration resection, min against for concentrations 30.5 ƒÊg/ maximum concerning be the of 33.3 capsule, underwent of concentration prostate, prostatectomy, values surgical who value penetration are concentrations patients were retropubic reached in serum. and/ or CPZ underwent lobes min. a of 133 min. patients right at 10.3 prostate administration High In serum to were liver 20ml of surgery transure- prostatectomy. CPZ concen- prostatectomy. concentrations VOL.35 Fig. 1 NO,1 Age distribution CHEMOTHERAPY and surgical Mean age 17 procedure Fig. 2 Two-compartment CPZ concentration open model of serum 70.4 yrs. √V:5.7 but of CPZ, we used a fragments of prostatic tissue obtained by TUR or specimens from the prostatic capsule and each of the lateral lobes removed by open prostatectomy. The prostatic tissue was washed in a saline solution to eliminate blood and urine and frozen until the analysis was performed. The prostatic tissue CPZ concentration was determined from the degree of inhibition of Micrococcus luteus (strain ATCC 9341) on a thin-layer disc containing nutrient fluid. The prostatic tissue was homogenized in a 1/ 15M phosphate buffer (pH 7.0) and centrifuged at 3,000 rpm for 30 min. Using the supernatant, we measured the intraprostatic CPZ concentration by the same method as that used for serum. In the pharmacokinetic studies of the serum and intraprostatic CPZ concentrations obtained were from a single determination of each sample. The pharmacokinetic data were analyzed with a NEC ACOS 250 computer by the simulation and simplex method. Serum CPZ concentration was measured by a two-compartment model according to the calculation shown in Fig. 2. We employed the model in Fig. 3 to estimate the penetration of CPZ into prostatic tissue, which we considered to be related to its concentration in serum. We then applied a constant so that the square sum of the difference between the obtained value and the theoretical value would be minimal. In addition, the duration of serum and prostatic CPZ concentrations at each stage were computed in terms of the bacterial inhibitory concentration by the Newton- Raphson method. The area under the curve (AUC) was also computed by numerical integration according to Simpson's rule. The dose required to sustain a given concentration in serum and in prostate for 1.5 hours was calculated by the golden section method. C1 : Serum concentration (ƒÊg/ ml) V: Distributionvolume of compartment 1(1) K01 : Elimination K12. K21 : Transition W : Dose(mg) t : Time (hr) rate constant (hr-1) rate constant (hr-1) Fig. 3 Model of drug transport and nrostatic tissue C3 Ki3, K31: between serum Drug concentration (ƒÊg/ g) Transition rate constant (hr-1) RESULTS 1. Serum The ble CPZ 1. The biological CPZ values of 105.5 ƒÊg/ point) and time parameters distribution half-life serum space 133 min. concentration, ml 26.0 ƒÊg/ are was shown at 9 min ml at listed 5.7 L in (the 360 min in Ta- and A simulation the curve Fig. of 4, yielded minimum time (the maximum point). 2. CPZ In Table subdivided ple concentration pharmacokinetic concentration 1 the in prostatic prostatic according tissue pharmacokinetic to preparation data and tissue are sam- site. With tration open in prostatectomy, the right lobe, the maximum 33.3 ƒÊg/ g, was concenattained CHEMOTHERAPY 18 Table I Pharinacokinetic JAN, 1987 parameters Serum Cw= A1e- α1+ Prostatic Cw= A2β1 tissue B1ek31- 1+ B2eα1+ B3e.-β1 Fig. 4 at 8.6 was Simulated mean serum CPZ after 1 g intravenous concentration injection min The after 3.52. administration. The concentration ed a maximum ministration. surgical The capsule, was also the highest left lobe at 8.6 K31/ K13 ratio μg/ g at 10. 3 min. which g, Fig. 5 Simulated mean right lobe concentration of CPZ after 1 g intravenous injection K31/ K13 ratio in the of 30.5 ƒÊg/ of was min reach- concentration Fig. 6 Simulated mean left lobe concentration of CPZ after I g intravenous injection (64.2) postad- 3.85. In was the 34.3 The K31/ K13 ratio was 3.29, smaller than that for the adenomatous lobes. In the case of tration, 39.8 ƒÊg/ occurred very The K31/ K13 The after ratio tissue shown similar g, in course, reaching the in with the CPZ concen- adenomatous min-after tissue administration. 3.69. curves were Figs. maximum resected was simulation prostatic are TUR, soon-2.3 for CPZ derived 5-8. All concentrations maximum. concentration in from these four curves data depict and slowly declining a VOL.35 Fig.7 3. Duration of (MIC) The are and 33 lobe min. 4. The AUC μg/ml which the prostatic in prQstate, concentration A level 2. was of 12.5 for remained peg over was of above A concentration maintained 2 of 25.0ƒÊg/ duration concentrations tissue Table in serum regions the surgical inhibitory Simulated mean TUR tissue concentration of CPZ after 1g intravenous injection was g was In AUC sustained 58 min- in for prostatic for and serum 5. for trations the In was concentrations is given large: 160. 9ƒÊg/ hr/ ml in 314.5ƒÊg/ at 25.0ƒÊg/ in Table 3. Table In 2 Duration 25.0ƒÊg/ to of for 1.5 hours drug 1.18g g was and the hr/ g, of 61.40 AUC was g, the MIC maintain a concentration In in average for 1.5 4) to drug. iarge of 75.22μg/ maintain required of was an are listed concen- in Table 4. of 100ƒÊg/ ml necessitated the surgical required 2.35g various for capsule for a level a of the pros- concentration of of 50ƒÊg/ g. DISCUSSION 3.13 the at (Table serum, 25.0ƒÊg/ AUC average with dosages The hr/ ml at ml. se- the an required hours The tate, CPZ tissue g, with ieft lobe, Dosage left 3) several in μg/ hr/ g. However, srnall in all sites. in the 3.13μg/ capsule, small 1.44g (Table AUC and 2 hrs detected hrs. longer- of for capsule. and at surgical a concentration 28min; rum or listed of CPZ prostatic minimal 19 Fig. 8 CPZ during in serum MIC 50 ƒÊg/ ml all of intervals CPZ the CHEMOTHERAPY NO.1 Simulated mean surgical capsule concentration of CPZ after 1g intravenous injection Inflammation of the prostate clinicians. Patients with by of MIC maintenance is often prostatitis encountered range wide- CHEMOTHERAPY 20 JAN. 1987 Table 3 The area under the concentration/time curve Table Dose required 4 to maintain ly in age, from adolescents to the elderly. If detected early, acute inflammation can be controlled with antibiotics. However, in some cases the inflammation is not cured but advances to a chronic state, and the treatment period may be prolonged, to no effect. The main problem is that few antibiotics reach the prostate in high enough concentration to exert a bacteriocidal effect on the prostatitis-causing organisms. Newly developed antibiotics are always studied for their efficacy against prostatitis, particularly in terms of their ability to penetrate the prostate. Their penetrative capacities should be evaluated in patients with prostatic inflammation, but in fact have generally been assessed in patients with prostatic adenoma, following drug MIC for 1.5 administration and vestigation we trations tatic of tive. lished in and et al5). into results', and surgical excision. simultaneously CPZ capsule, MIYATA factorily hours However, to on that prostate. suggested reports this the tissue, in- concenthe pros- serum. reported the In measured adenomatous the data CPZ We that diffused satis- presented CPZ similar is clinically there have been pharmacokinetics effecno of CPZ pubwith- in prostate. Our 1) nomatous g and travenous results The are CPZ lobes summarized concentration reached 33. 3 ƒÊg/ g, respectively, administration. as in maximum follows. right and levels at 8.6 min left ade- of 30 .5ƒÊg/ after in- VOL.35 2) sule CPZ concentration required attain its than more in the surgical time- of 34.3ƒÊg/ that g, 10.3 which adenomatous In adenomatous maximum in somewhat maximum ly higher 3) CHEMOTHERAPY NO.1 The tissue concentration min- was by higher, 1. cephalexin, to zole- slight- TUR, 39.8ƒÊg/ in reached earlier, istration, than When tic the at in tissue currently efficacy, min after resected were with penicillin- G by from the of drug by accepted which study 2.3 open criteria derived et al7), EAGLE6) are and associates and applied to this tis. by cause effectiveness against inflammation, 50ƒÊg/ ml Table since is sustained 2. This rum antibiotic tant element a serum for theory, over drug bacteria 2 hrs, as that ignores in only se- concentration the impor- within in tissue- 20: the tissue a factor that tration of can as the impossible was addressed an antibiotic in concentration that achived However, be in acute increase to by measure benign prostatic inflammation vascular perfusion be antibiotics tissue. med Therefore, prostate, against than greater we bacteria 02.5ƒÊg/ that for J. may per- 7) which the data to CPZ MIC prostatic the is of and reported infla- be for Serratia, bacter, calis and are often benign prostatic of CPZ against μg/ml in Pseudomonas, Klebsiella every species detected in urine hyperplasiam. these Proteus, and bacteria is less case12), CPZ after Med. lower seems capable & N. M. HI- Y. KATAYAMA: Entero- the for and based 10) MIC with between N. Engl. 1953 Dosage in schedule in sepsis proposed vitro- in results. Saishin- Prostatitis. Urol. dosage vivo experi- Igaku 32: 1977 2: 3•`27, Clin. N. 1975 Problems prostatitis; and mixed in diagnosis gram- negative, infection. J. of bactegram- Urol. posi- 111: 630 1974 OHKAWA, M.; M. SHIMAMURA, MIYAZAKI& chronic of ganisms. con- interval efficacy. the clinical "Con- therapy of cephaloridine on Nishi 1981 M. LEVY T. INAMATSU: DRACH, G. W.. 636, cefoperazone. 481•`488, between and than 12.5 trolling the majority of these organisms and is considered clinically useful. Acknowledgments: The authors are grateful to Mt. MASASHINOGUCHI, Department of Technology, Toyama Chemical Industry Co., Ltd. for his helpful suggestions in the pharmacokinetic analysis of CPZ. References 1) ADACHI,B.: Study of prostatic tissue and seminal plasma levels of chemotherapy agents. 248: MEARES, E. M.: tive fae- of "discontinuous" cephalothin Am. operation Although 87•`93, MATSUMURA, 414•`418, The effect on therapeutic 1497•`1504, 9) prostati- Streptococcus is not 29: gland H. TAKAMOTO, K. NANBA 43: SHIMADA, K.& rial tis8•`10). N. the Jpn. Y. R. FLEISCHMAN& vs ments epidermidis responsible FUJII, prostatic between Urol. levels Urol. schedule effective CPZ Staphylococcus to prostatiH. E. ISHIZUKA& T. ARAKI, relationship 8) coli been our Acta. tissue J. penicillin. injections ml. Escherichia have applying conclude of 1982 Difference K.; EAGLE, H.; tinuous" prostate to 70: Current cefoperazone T. TANAHASHI, same permeability, access of A. KONDO, ; nor hyperplasia. of the and the 6) of mitting Urol. I. KONDO, A. IWASAKI, capsule. MIYATA, ISHITO, in- concen- prostate to J. CUNHA SHIMA- the inflamed assumed ery- sulfame- 1983 Nihon is clinically fluid of therapy MIURA, study levels: and 5) al7). It Jpn. 338•`345, T. A Prostatic DA et prostatic methylch- B. A. antimicrobial Urology FUKUSHIMA, S.; RANO, flamed and Concentrations and A. M.& KITAJIMA: of shown concerns and 596•` de- concentration however, concentration of many 2. trimethoprim. M. HIROKAWA, monstrates 69: of chemothera- 1979 RISTUCCIA, concepts and agent Urol. aminobenzylpenicillin, 403•`409, 3) cephalothin CPZ, levels tissue plasma. thoxazole- antibio- experiments 4) SHIMADA J. of sulfamethoxa- lorophenylisoxazolylpenicillin, surgery. for from cephaloridine admin- Jpn. Study prostatic or seminal g, and thromycin, was and 1978 SAKURAGI, T.: peutics the doxycycline trimethoprim. 603, 2) tissue. resected was 21 cap- K. KURODA: prostatitis, T. MISAKI, Clinical especially Rinsho Hinyokika K. studies of of isolated 29 or- 771•`776, 1976 11) SAITO, & I. KONDO: of surgery pertrophy. Nishi 996, 12) K. prognosis N.& antibacterial ous als. infection benign J. and prostatic Urol. 44: hy989•` 1982 KOSAKAI, 1551) Urinary for Nihon with T. OGURI: activity other pathogens Chemotherapy Comparison of cefoperazone cephalosporins isolated from 28(S- 6) against clinical 14•`27, of the (Tvari- materi1980 CHEMOTHERAPY 22 JAN. 前 立 腺 肥 大症 患 者にCefoperazone(CPZ)one shot静 1987 注後の血中 お よび 前 立 腺 組 織 移 行 濃 度 の 薬 動 力学 的 解 析 福島 修 司 ・三 浦 猛 ・菅 原 横浜市立市民病院泌尿器科 敏道 近 藤 猪 一 郎 ・藤 井 浩 神奈川県立成人病センター泌尿器科 広 石 川 信 ・岩 崎 藤沢市民病院泌尿 器科 塚 栄 一 ・北 島 晧 直 登 横浜赤十字病院泌尿器科 CPZ 1gを 前立腺肥大症患 者53名 の手術前に静注 し,血 清および摘 出前立腺 組織内濃度を測定し,薬 動力学 的解析を試みた。 血 清濃度は高 く維持 され,生 物学的半減期(T1/2β)は133分 であ った。 恥骨 後式前 立腺摘出術施 行例の 前立 腺組織は 左右両葉 とも8.6分 で最高濃度に達し,そ の濃度は30.5μg/g,33.3μg/gで あった。被膜は10.3分 で最高濃度に達 し,そ の濃度は34.3μg/gで あった。経尿道的 切除例では2.3分 で最高濃 度39.8μg/gに 達 し ていた。 どの部位 も血清濃度の低下とともに下降 し,同 様な濃度推移を示した。 時 間曲線下面積お よび各部位の濃度の推 移をみ ると,前 立腺炎の起炎菌や前立腺 肥大症 の術後に検 出され る細 菌に対して有効性が高いと判断された。
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