Comparison of plasma levels of canrenone and metabolites after base hydrolysis in young and elderly subjects following single and multiple doses of spironolactone

Summary Plasma levels of canrenone and total metabolites after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on Day 1, plasma levels of canrenone and total metabolites were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and total metabolites. However, these differences between the two age groups diminished after multiple dosing on Day 8, and the steady state predose plasma levels of canrenone and total metabolites were significantly higher in the elderly subjects. The accumulation ratios of canrenone and total metabolites were significantly higher in the elderly than in the young subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as 1.) a proportionate shift in metabolism with age; 2.) impaired oral absorption of the parent compound; and/or 3.) altered volume of distribution of the drug.     

Kinetics of canrenone after single and multiple doses of spironolactone

Summary In Study I 20 normal volunteers received a single oral dose of spironolactone 100 mg. In Study II a further 20 normal volunteers were given first spironolactone 100 mg b.i.d. and subsequently spironolactone 100 mg once a day for a further 4 days. In Study III 5 normal subjects were given a single dose of spironolactone 500 mg. The concentration of canrenone in serum was determined both by fluorimetry and HPLC for 0–48 h in Study I, 120–168 h in Study II and 0–36 h in Study III. The total AUCs after the single 100 mg dose did not differ from the AUCs within the dosing interval during steady state. The half-lives of the terminal log-linear phases were almost identical (14.99±0.80 h and 15.69±0,80 h) when determined by fluorimetry, and were sligthly, but significantly (p<0.01), longer when determined by HPLC — 20.14±1.62 and 18.71±1.04. The mean ratio of the specific AUC determined by HPLC and the fluorimetrically determined AUC was 0.3 after the single 100 mg dose. It did not differ from the corresponding value during steady state (0.34). In contrast, the ratio after the single 500 mg dose was approximately 50% higher. Fluorimetrically determined AUCs after 100 and 500 mg doses did not show dose-proportionality in contrast to the HPLC-determined AUCs. It was concluded that Canrenone contributes much less to the conventional fluorimetric determination than was previously assumed. It may not provide more than 1/10 and 1/4 of the antimineralocorticoid activity of spironolactone after single dose and multiple doses, respectively. Whereas linear kinetics apply after single and multiple 100 mg doses of spironolactone, after 500 mg saturation kinetics must be assumed with respect to metabolism. Thus, in bioavailability studies high doses of spironolactone should be avoided. For such studies the fluorimetric assay seems to be the appropriate bioanalytical method in spite of its lower specificity.First presented at the 20th Spring Meeting of the German Pharmacology Society, Mainz, March 20–23, 1979.     

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium

Summary The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC.The mean C_max of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg.With 4-AA, the increase in mean C_max was linear, but the increase in AUC was not.The increases in mean C_max and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose.The increases in mean C_max and AUC for 4-AcAA were roughly proportional to the increase in dose.There were no significant differences in renal clearance between doses for any of the four metabolites.The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.     

螺内酯代谢物血药浓度的测定及健康人体药动学

目的:建立反相高效液相色谱法测定螺内酯的代谢物——坎利酮的血药浓度,并研究其在健康人体的药动学。方法:以乙酸乙酯为萃取溶剂,采用 Hypersil C_(18)柱(4.6 mm×250 mm,5 μm),流动相:乙腈-0.02 mol·L~(-1)磷酸氢二铵溶液(45:55);流速为1.0 mL·min~(-1),检测波长为280 nm。结果:坎利酮在9.375～300μg·L~(-1)范围有良好色谱响应线性关系(r=0.9999),提取回收率均大于73.3%,日内与日间 RSD 均小于4.8%。人体药动学参数 C_(max)为(172.1±43.3)μg·L~(-1),T_(max)为(4.0±1.2)h,T_(1/2ke)为(16.8±4.3)h,AUC_(0-t)为(3246.1±800.4)μg·h·L~(-1),AUC_(0-∞)为(3649.1±960.4)μg·h·L~(-1)。结论:本方法是测定螺内酯活性代谢物——坎利酮血药浓度的可靠定量方法,适用于螺内酯的人体药动学研究。     

Pharmacokinetics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, after single oral dose administration in Chinese healthy male volunteers

Antofloxacin hydrochloride is a newly developed fluoroquinolone antibacterial in China, which has comparable in vitro and animal pharmacological and toxicological properties to levofloxacin and is worthy of further clinical trial. Human tolerance of single escalating doses from 50 to 500 mg was shown to be safe. The purpose of the present study was to evaluate the pharmacokinetic characteristics of a single oral dose of antofloxacin hydrochloride in Chinese healthy male volunteers. Twelve subjects were randomized for administration of a single dose of 300, 400 and 500 mg antofloxacin hydrochloride in a 3-way crossover design. High pressure liquid chromatography (HPLC) was used to assay the serum and urine concentrations of antofloxacin in samples collected over a period of 72 h following drug administration. All three dosages were well tolerated. Antofloxacin hydrochloride demonstrated linear pharmacokinetic characteristics with mean pharmacokinetic values varying from 0.09 to 0.10 l/h/kg for CL/F and from 2.75-3.00 l/kg for V/F. The t(1/2beta) was around 20 h and the mean fraction of dose excreted in urine varied from 0.40 to 0.46. Based on these data, 300 mg of antofloxacin hydrochloride administered once daily was selected for further investigation in a multiple dose administration study.     

Pharmacokinetics of ketoprofen following single oral,intramuscular and rectal doses and after repeated oral administration

Summary The pharmacokinetics of ketoprofen was studied in the same healthy subjects after single oral, intramuscular and rectal doses, and after repeated oral administration. No significant difference in the mean t_1/2 (1.13–1.27 h) was observed after the different modes of administration. The mean [AUC] ₀ after rectal administration of a suppository showed the minimum significant difference (p<0.05) from that after oral administration of the capsule. The apparent volume of distribution (Vd/F) was approximately 10–15% of body weight. The renal contribution (mean, 0.10–0.15 ml/min/kg) to the plasma clearance of free ketoprofen was assumed to be, at most, 8.3–12.9%. The projected cumulative excretion of total (free plus conjugated) ketoprofen via urine exceeded 63–75% of the dose, of which approximately 90% was ketoprofen glucuronide. A mean of 71–96% and 73–93% of the oral capsule was estimated to be systemically available after administration of the intramuscular preparation and rectal suppository, respectively. In four of seven subjects, CPK concentration was elevated after the intramuscular injection. The mean steady-state concentration of ketoprofen in plasma ranged from 0.43 to 5.62 µg/ml after the final dose of a 50 mg q.i.d. regimen. The disposition data and plasma levels observed at steady-state were in agreement with those predicted from the single oral dose study. The accumulation ratio was 1.08±0.08. The results suggest that the rectal suppository can be recommended as an extravascular mode of administration of this drug.A preliminary account of this work was presented at the 10th Congress of Japanese Society of Clinical Pharmacology, Sapporo, 27 August 1979     

盐酸小檗碱单次和多次给药在Beagle犬体内的药动学

目的研究盐酸小檗碱胶囊单次和多次给药后在Beagle犬体内的药动学。方法 6条Beagle犬按150 mg单次和多次口服盐酸小檗碱胶囊,多次给药每天1次,共7 d。采用UPLC-MS/MS色谱法测定犬血浆中盐酸小檗碱的浓度。用DAS 2.0药动学软件处理血药浓度数据。用SPSS统计软件对所得的药动学数据进行显著性差异分析。结果单次给药后主要药动学参数t1/2为(18.85±10.54)h,ρmax为(4.18±2.59)μg.L-1,AUC0-t为(110.04±70.22)μg.h.L-1,AUC0-∞为(121.51±74.19)μg.h.L-1,CL为(1 593.57±745.01)L.h-1,V为(44 509.1±34 995.4)L,tmax为(20.42±22.98)h;多次给药达稳态后主要药动学参数t1/2为(18.53±9.99)h,ρmax为(9.92±7.01)μg.L-1,AUC0-t为(164.51±119.70)μg.h.L-1,AUC0-∞为(172.34±125.03)μg.h.L-1,CL为(1 280.19±709.95)L.h-1,V为(33 655.7±27 632.2)L,tmax为(6.08±4.90)h。结论盐酸小檗碱单次和多次给药后在Beagle犬体内血药浓度均较低,盐酸小檗碱多次给药在Beagle犬体内无明显蓄积现象。     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

1. The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen.

2. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time.

3. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C_max 3.81?±?0.66?mg/L, C_min 0.85?±?0.19?mg/L, AUC_0–24 60.51?±?8.30?mg/L·h, C_av 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t_1/2β 20.34?±?1.88?h. The C_max and AUC_0–24 after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%.

4. During the study, there were neither subject complaints nor significant adverse clinical findings.

5. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.

     

Pharmacokinetics of sulphinpyrazone and its major metabolites after a single dose and during chronic treatment

Summary The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t_1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t_1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.Abbreviations k_a first order rate constant for absorption or appearance - k_el first order rate constant for elimination - F extent of bioavailability - D administered dose (as free base) - k₁₂ first order distribution rate constant into peripheral compartment - k₂₁ first order distribution rate constant from peripheral compartment - k₁₀ first order elimination rate constant from central compartment - first order elimination rate constant of rapid disposition phase - first order elimination rate constant of slow disposition phase - V_z apparent volume of distribution - V_c apparent volume of distribution of central compartment - t time after drug administration - t_o lag time for absorption - Cp_(t) concentration in plasma at time t - n number of doses - Cp_(tn) concentration in plasma at time t after n^th dose - dose interval - CL clearance uncorrected for bioavailability F     

Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects

Summary The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t_1/2 of the elimination phase () was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h^–1 and the plasma carnitine clearance was 5.4 vs 6.11 · h^–1 for the 2 g and 6 g doses, respectively, showing dose-related elimination. Saturable kinetics were not found. The apparent volumes of distribution after the two doses were not significantly different and were of the same order as the total body water. Urinary recoveries of the 2 g and 6 g doses were 70% and 82%, respectively, during the first 24 h. Following the oral doses, there was no significant difference between the areas under the plasma carnitine concentration-time curves. Urinary recovery was 8% and 4% for the 2 g and 6 g doses during the first 24 h. Oral bioavailability was 16% for the 2 g dose and 5% for the 6 g dose. The results suggest that the mucosal absorption of carnitine was already saturated by the 2 g dose.     

健康男性多次口服爱地那非片的药代动力学和安全性

目的 研究中国男性健康受试者多次口服枸橼酸爱地那非片(治疗阴茎勃起功能障碍)的安全性和药代动力学.方法 27名受试者随机分为30、45和60 mg 3个剂量组,每组9人,试验期间严密观察临床症状体征和不良事件,用LC-MS/MS测定多次服药后血浆中的药物浓度,并计算药代动力学参数.结果 受试者多次口服枸橼酸爱地那非片30、45和60 mg后,其主要药代动力学参数:Cmax分别为(256.6±106.6)、(435.7±115.4)和(918.6±442.5)ng·mL-1;Cav分别为(57.2±26.1)、(95.0±28.9)和(247.6±137.0)ng·mL-1;tmax分别为(1.1±0.6)、(1.2±0.6)和(1.6±0.5)h;t1/2分别为(4.5±0.3)、(4.4±0.6)和(3.9±0.6)h;AUC0-24h分别为(1373.3±625.6)、(2280.1±693.6)和(5941.8±3288.4)ng·h·mL-1;AUC0-36h分别为(1405.9±650.2)、(2314.6±710.3)和(6039.9±3 338.4)ng·h·mL-1.药物不良反应主要为面色潮红、头痛或头晕等,程度均为轻度.结论 连续3天,每天1次,口服枸橼酸爱地那非30～60 mg对健康受试者是安全的,爱地那非在体内无明显蓄积;在30、45 mg时,Cmax和AUC0-t与剂量成比例增加;而在60 mg时,呈非线性药代动力学特征.     

螺内酯片健康人体药动学及生物等效性评价

目的:研究螺内酯在中国健康人体内的药动学和生物等效性。方法:采用随机双周期交叉设计, 18名健康志愿者单剂量口服200 mg螺内酯,HPLC法测定血浆中螺内酯的代谢物坎利酮的浓度。结果:参比制剂和受试制剂药-时曲线均符合一房室模型,受试制剂和参比制剂的代谢物坎利酮的药动学参数如下:t_(mux)分别为(4．2±s 1．2)和(4．7±1．6)h,C_(mux)分别为(160±47)和(150±43)μg·L~(-1),t_(1/2ke)分别为(18±5)和(19±4)h,AUC_(0～72)分别为(3168±688)和(3267±627)μg·h·L~(-1),AUC_(0～∞)分别为(3611±768)和(3759±642)μg·h·L~(1-)。与参比制剂相比,受试制剂的相对生物利用度为(106±26)％。结论:所建立的方法适用于螺内酯的人体药动学研究;经方差分析和双向单侧t检验证明,2种制剂具有生物等效性。     

Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers

Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.     

Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model

Acebutolol (AC), is a chiral, β -adrenergic blocking agent which possesses partial agonist activity and is metabolized to an equipotent chiral metabolite, diacetolol (DC). The enantiomeric disposition of AC is reported following racemic administration as a single oral (p.o., 50 mg kg⁻¹) or as a multiple thrice daily intravenous (i.v.) or p.o. dosing for four days in male Sprague–Dawley rats (n =6). Enantiomeric concentrations of AC and DC in plasma and urine were determined using a stereospecific HPLC assay. The bioavailabilities of R- and S-enantiomer were 0.40 and 0.39 after single dose administration of AC respectively. These values were increased to 0.51 and 0.53 after multiple dosing. Although no significant differences were found in AUC_0–∞ after single i.v. as compared with AUC_0–τ after multiple i.v. dosing of AC, the 39 and 45% increase in mean AUC_0–τ were found after multiple p.o. dosing over the corresponding AUC_0–∞, for the single p.o. dose of AC for R- and S-enantiomer, respectively. The disposition of DC as well as the urinary excretion of metabolite was stereoselective in favor of R-enantiomer after oral administration of AC. These results indicate that AC enantiomers have low availability and moderate extraction through the first-pass metabolism in a rat model. The higher AUC values after p.o. multiple dosing may suggest a saturable first-pass metabolism of AC. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetics of cimetidine after subchronic administration

Summary The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26–29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t_1/2 and V were similarly unchanged. However mean renal clearance (CL_R) and f_e were significantly increased following 2 weeks of drug dosing (CL_R 5.41 ml·min^–1 kg^–1; f_e 0.61) compared to control (CL_R 4.00 ml·min^–1·kg^–1; f_e 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min^–1·kg^–1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.     

Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing

AIMS: The pharmacokinetics of dihydrocodeine (DHC) and its active metabolite dihydromorphine (DHM) were assessed after a single oral dose of DHC and after increasing doses of DHC at steady-state. Methods Twelve healthy male volunteers (18-45 years, CYP2D6 extensive metabolizers (EMs), MR<1 took a single oral dose (s.d.) of DHC 60 mg after breakfast. After 60 h DHC 60 mg was administered twice daily for 3 days, the dose was increased to 90 mg twice daily for 3 days, the final dose of 120 mg was administered twice daily for 3 days (multiple dose: m.d.). Blood sampling and urine collection: during 60 h after s.d. and during 12 h after m.d. Results No significant differences in the area under the curve (AUC) of both, DHC and DHM could be detected after a single oral dose of 60 mg DHC (AUC (0,infinity)) and during steady-state doses of 60 mg DHC (AUC(0,12 h)). During increasing steady-state doses of DHC, the data showed a dose linearity of AUC, maximal serum concentration (Cmax ) and minimal steady-state serum levels (Cssmin) of both, DHC and DHM (P<0.0001), point estimates of DHC dose corrected AUCs were well within the bioequivalence range (60 mg: 0.989; 90%CI 0.951-1. 028, 90 mg: 0.997; 90%CI 0.959-1.036, 120 mg: 0.977; 90%CI 0.940-1. 016). O-demethylation from DHC to DHM remained constant within the increasing steady-state doses of DHC in the 12 extensive metabolizers of CYP2D6. CONCLUSIONS: In the studied dose range (60-120 mg) the pharmacokinetics of DHC and its active metabolite DHM are linear in EMs of CYP2D6.     

Influence of dose and route of administration on disposition of metronidazole and its major metabolites

Summary The influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p<0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.     

Pharmacokinetic of 2-(p-methylallylaminophenyl) propionic acid,alminoprofene, in man after single and multiple oral doses

Summary 2-(p-methylallylaminophenyl) propionic acid, alminoprofene (INN), a new antalgic drug, was administered orally to men as a single (300 mg) and multiple doses (300 mg three times daily). Plasma and urine concentrations of alminoprofene were determined by gas-liquid chromatography. After the single oral dose, the peak plasma level (36.2 to 41.5 mg/l) was reached within 0.5–1.5 h. The biological half-life ranged from 2.5 to 3.2 h. During chronic administration of alminoprofene, steady-state equilibrium quilibrium was etablished within 24 h. The urinary excretion of alminoprofene as unchanged product and as glucuronide was very important.     

Pharmacokinetics and tolerance of a new penem antibiotic,FCE 22101, in healthy volunteers after a single intravenous dose

Summary The clinical tolerance and pharmacokinetics of FCE 22101 (sodium (5R, 6S)-6-[(1R)-hydroxyethyl]-2-carbamoyloxymethyl-2-penem-3-carboxylate), a new penem antibiotic, have been studied after giving a single i.v. dose of 4 mg·kg^–1 to ten healthy male volunteers. The pharmacokinetics was estimated according to a two-compartment open model. The peak plasma concentration (C_max) was 15.5 (1.08) µg·ml^–1, mean (SEM). FCE 22101 was rapidly cleared from the systemic circulation [ =44.2 (4.2) min; CL=7.21 (0.47) ml·kg^–1·min^–1]. The mean apparent volume of distribution at steady-state was 246 (16.9) ml·kg^–1. The mean residence time relative to the 10 min infusion was 39.4 (1.5)min. Urinary recovery of FCE 22101 showed wide inter-subject variation, ranging from 10.2 to 53.6% of the dose. No subject complained of adverse effects.     

Chlorpromazine metabolism. IX. Pharmacokinetics of chlorpromazine following oral administration in man

A single oral dose (120 mg/m²) of Chlorpromazine hydrochloride was administered to four healthy subjects and the blood levels of Chlorpromazine were determined with time. Appropriate equations describing the two-compartment open model with zero-order absorption and the two-compartment model with first-order absorption, both with a lag time, were fitted to the observed data using weighted nonlinear least-squares regression analysis. Fitting the two-compartment model with zero-order absorption and a lag time to the observed data resulted in a significant reduction of the weighted sum of squared deviations, i.e., better correlation between the observed and calculated data, and a closer random scatter of the observed concentration data around the calculated curve with no apparent systematic deviations from the curve. These results suggest that Chlorpromazine absorption is zero order. Chlorpromazine began to appear in the systemic circulation after a mean lag time of 0.4 hr and continued to be absorbed for approximately 2.9 hr. The mean half-lives of the distribution and elimination phases were 1.63 and 17.7 hr, respectively.This work was supported in part by National Institute of Mental Health Grant No. MH 21408-02, NIH.Presented by L. Whitfield at the Twenty-third National Meeting of the APhA Academy of Pharmaceutical Sciences, November 13–17, 1977.