Effect of hepatic cirrhosis on the pharmacokinetics of theophylline in rats

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethylnitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life (t_1/2) in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL (8.67±4.85%) decreased about four-folds, but in DMNA (73.00±9.85%) similar result, was observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.     

The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis

Aims To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide. Methods We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child-Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg⁻¹ was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c. Results The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T₁:T₀, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T₁:T₀, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T₁:T₀, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T₄:T₁ to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg⁻¹ min⁻¹; P<0.005). The central (V₁ ) and steady state volumes of distribution (V_ss ) did not differ significantly between the groups. The slow redistribution (t½,λ1 ) and elimination (t_½,z ) half-lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P<0.005; and 143 (80) vs 92 (40) min, P<0.05 respectively). The exit rate constant for the effect compartment k_eo was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min⁻¹; P<0.05), but cirrhosis had no significant effect on the parameters of the concentration-effect relationship Cp^ss50 and γ. Conclusions Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.     

盐酸贝那普利大鼠在体小肠吸收动力学

目的:研究盐酸贝那普利在大鼠小肠的吸收情况。方法:采用大鼠在体小肠回流实验装置,测定盐酸贝那普利的吸收动力学与透过速率常数,研究在不同浓度下盐酸贝那普利的吸收机制。结果:小肠是盐酸贝那普利的吸收最佳部位。盐酸贝那普利在低、中、高3种不同浓度下,透过速率常数分别为0.789,0.810,0.766,无显著差异。结论:盐酸贝那普利吸收机制为被动扩散。吸收动力学为一级吸收。     

The pharmacokinetics and pharmacodynamics of perindopril in patients with hepatic cirrhosis.

1. Perindopril, a new ACE inhibitor, is a prodrug requiring conversion into its active form perindoprilat by hydrolysis in the liver. 2. The pharmacodynamics and pharmacokinetics of perindopril (8 mg oral) and perindoprilat (2 mg intravenously) were studied in a double-blind randomised crossover study in a group of patients with compensated biopsy-proven hepatic cirrhosis. 3. Blood pressure and heart rate responses were similar after the two routes of administration as were plasma renin activity and aldosterone levels following dosing. 4. The AUC of perindoprilat after oral administration of perindopril represented 46 +/- 4% of the total AUC of perindopril and its metabolite when expressed in molar terms. Comparison with the AUC of perindoprilat after its intravenous administration suggested that 30 +/- 6% of the oral dose of perindopril was converted to its active metabolite. 5. The findings are comparable with those in healthy subjects. It appears that the presence of relatively mild hepatic cirrhosis does not significantly alter the pharmacokinetics of perindopril.     

Single-dose pharmacokinetics of nateglinide in subjects with hepatic cirrhosis

This single-dose, open-label, parallel-group study compared the pharmacokinetics and tolerability of 120 mg doses of nateglinide, a physiologic mealtime glucose regulator for type 2 diabetes, in 8 subjects with cirrhosis and 8 matched healthy subjects. In both groups, plasma concentration peaked in a median of 0.5 hours, and mean terminal elimination half-lives were comparable. Mean +/- SD pharmacokinetic parameters in cirrhotic versus healthy subjects were slightly different (Cmax, 7.7 +/- 4.9 vs. 5.6 +/- 1.3 micrograms/ml; AUC(0-t), 18.5 +/- 7.5 vs. 14.2 +/- 2.1 micrograms.h/ml, respectively). Mean apparent total clearance and mean renal clearance in both groups were comparable. Mean protein-bound fractions were equivalent; binding appeared unaltered by metabolites. One cirrhotic and 2 healthy subjects each reported one adverse event. No statistically significant or clinically relevant alteration in pharmacokinetic parameters of nateglinide resulted from hepatic dysfunction, and it was well tolerated; therefore, adjustment of nateglinide dosage is not required in subjects with mild to moderate cirrhosis.     

短期合用缬沙坦与盐酸贝那普利对高血压患者药代动力学与药效学的影响

目的探讨短期合用缬沙坦与盐酸贝那普利（抗高血压药）的药代动力学与药效学.方法16例原发性高血压病人分为缬沙坦单用组和联合用药组,单用组口服缬沙坦每天80 mg,合用组口服缬沙坦每天80 mg、盐酸贝那普利每天10 mg,2组均连服7天;测定服药第7天缬沙坦血药浓度;观察服药前后24 h动态血压、肾素-血管紧张素-醛固酮系统（RAAS）各组分、肾功能及血钾变化.结果主要药代动力学参数Cmax,tmax,t1/2,AUC 2组比较均无统计学差异;服药后,降压幅度合用组显著优于单用组;短期服药后,2组RAAS系统各组分变化均无统计学意义;服药后,肾功能及血钾单用组无显著变化,合用组血钾显著降低,但变化在临床正常范围内.结论短期合用盐酸贝那普利对缬沙坦药代动力学参数无显著影响;合用降压作用起效快,降压幅度优于单用缬沙坦,且较安全.     

HPLC法测定复方盐酸贝那普利片中盐酸贝那普利和苯磺酸氨氯地平的含量

目的建立复方盐酸贝那普利片中盐酸贝那普利和苯磺酸氨氯地平含量测定的HPLC法。方法采用Diamonsil C18柱(200 mm×4.6 mm,5μm);流动相为氯化钾溶液(1 000 mL中含90 mmoL氯化钾和10 mmoL盐酸,pH值2.06)-水-甲醇(体积比为17∶25∶58),每1 000 mL流动相中加入612 mg高氯酸钠;流速为1 mL.min-1;检测波长为240 nm;柱温为35℃;进样量为20μL。结果盐酸贝那普利与苯磺酸氨氯地平可达到较好分离,盐酸贝那普利的质量浓度在10.0～200.0mg.L-1内与峰面积呈良好的线性关系(r=0.999 8);苯磺酸氨氯地平(按氨氯地平计)质量浓度在5～100 mg.L-1内与峰面积呈良好的线性关系(r=0.999 8)。盐酸贝那普利与苯磺酸氨氯地平的平均回收率分别为99.9%(n=9)和100.4%(n=9)。结论 HPLC法适用于复方盐酸贝那普利片中盐酸贝那普利和苯磺酸氨氯地平的含量测定。     

The pharmacokinetics of teniloxazine in healthy subjects and patients with hepatic cirrhosis.

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CLo (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min-1 kg-1; mean % ratio between the two values (95% CI), 123 (94-151)) and a significant shortening of t 1/2 (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58-98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CLo was about halved in cirrhotic patients, whereas t 1/2 was more than doubled. As a consequence of these modifications, the multiple-dose regimen resulted in a two-fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.     

盐酸贝那普利的合成及精制

盐酸贝那普利是世界卫生组织推荐的一线抗高血压药物,是一种强效的血管紧张素转化酶抑制剂。本文介绍了盐酸贝那普利的合成及精制的工艺过程,所得产品经核磁共振、红外光谱确证结构。     

Effect of experimentally-induced hepatic cirrhosis on the pharmacokinetics of orally administered praziquantel in the rat

The effects of pretreatment with the hepatotoxin, thioacetamide, on the pharmacokinetics of praziquantel, a broad spectrum schistosomicidal agent with a high hepatic clearance, were studied in male Wistar rats. Animals were pretreated with either thioacetamide (25 mg in 100 ml of drinking water, n = 5) for 24 weeks or received plain drinking water (n = 5) over the same period. After the treatment period, praziquantel was administered orally (25 mg/kg as a 20 mg/ml solution in PEG 200) as a single dose. Blood samples (0.3 ml) were collected from the clipped tail at various times up to 4 h post administration. Plasma was analysed for praziquantel using an HPLC method. Mean peak plasma praziquantel concentrations were approximately 1.0 mg/l for both groups. The time to reach peak concentrations, and post-peak elimination half-life, were approximately 0.7 h and 1.0 h, respectively, for both groups. Similarly, mean AUC was approximately 2.0 mg.h/l for both groups. Statistical comparisons indicated that there were no significant differences in the pharmacokinetic parameters estimated in the two groups of animals. It was concluded that thioacetamide-induced hepatic cirrhosis has no effect on the pharmacokinetics of orally administered praziquantel in the rat, at the dose level studied.     

盐酸贝那普利产业化工艺研究

目的:探讨盐酸贝那普利产业化工艺.方法:以(R)-2-羟基-4-苯基丁酸乙酯为原料,经过酰化、缩合然后水解成盐制备盐酸贝那普利.结果:成品总收率为37.6%,并且质量检测结果符合中国药典质量标准的要求.并对产业化过程中(R)-a-(4-硝基苯磺酰氧基)-4-苯丁酸乙酯的合成工艺以及成品的精制工艺进行了考察.结论:本工艺收率较高,质量稳定,适于产业化生产.     

Omapatrilat in patients with hepatic cirrhosis. Pharmacodynamics and pharmacokinetics

OBJECTIVE: The pharmacodynamics and pharmacokinetics of omapatrilat, a member of a new class of cardiovascular compounds, the vasopeptidase inhibitors, were evaluated in subjects with hepatic cirrhosis (n = 10) and in healthy subjects (n = 10) matched for age, weight, gender and smoking history. METHODS: All subjects received omapatrilat 25 mg orally once daily for 14 days. Plasma renin and urinary atrial natriuretic peptide (ANP) levels were measured to assess the effect of omapatrilat on cirrhotic subjects. The effect of omapatrilat on blood pressure as well as changes in ANP and plasma renin levels were not altered by hepatic impairment. Pharmacokinetic parameters were determined from plasma omapatrilat concentrations. RESULTS: There were no significant differences between the two subject groups with regard to log-transformed area under the curve or maximum observed plasma concentration. Systemic accumulation was similar in the two groups. CONCLUSION: These results suggest, based on findings in otherwise healthy cirrhotic subjects, that no adjustment of standard dosing regimens is indicated for hypertensive patients with mild to moderate cirrhosis.     

The effect of liver cirrhosis on the pharmacokinetics of phenprocoumon

Summary Phenprocoumon was given orally to 9 patients with biopsy proven liver cirrhosis (dose range 0.12–0.25 mg/kg) and to 7 healthy volunteers (0.23 mg/kg). Concentrations of phenprocoumon were determined using HPLC in plasma and urine samples obtained for 6–7 days after drug administration. The binding of [³H]-phenprocoumon in plasma from all subjects was determined by equilibrium dialysis. Antipyrine plasma concentrations were determined spectrophotometrically following oral administration of antipyrine (1200 mg). The total body clearance of phenprocoumon was higher in the cirrhotic patients (1.64±0.16 ml/h/kg mean ± SEM) than in the healthy volunteers (0.90±0.07 ml/h/kg), however the free drug clearance was not significantly different in the patients (144±14 ml/h/kg) compared with normal (113±11 ml/h/kg). In contrast the clearance of antipyrine was much reduced in the cirrhotic group (17.5±2.9 ml/h/kg) compared with normal (35.6±3.9 ml/h/kg). The metabolic clearance of phenprocoumon via glucuronidation, is relatively unaffected during cirrhosis compared with antipyrine clearance via oxidation.     

Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide

Summary After rapid intravenous injection of furosemide 40 mg (Fu), plasma levels were determined in 7 healthy volunteers, 8 patients with liver cirrhosis with ascites and 7 patients with end-stage renal disease (ESRD). The diuretic response was evaluated by measuring the urinary excretion of sodium and potassium and the urine volume. The mean elimination half life (tF_1/2+) of Fu averaged 51±7.7 (±SD) min in healthy subjects, 52±7.7 min in cirrhosis and 200±57 min in ESRD. The non-renal clearance (Cl_nr) in healthy subjects (56±28 ml/min) corresponds to the total plasma clearance in functionally anephric patients (54±18 ml/min). In cirrhosis there was no significant change in the disposition parameters of Fu in comparison to the healthy volunteers, but there was a significant reduction in urine sodium and volume, whereas potassium excretion remained unchanged. Fu “excretion rate — response” curves showed diminished tubular sensitivity to Fu in cirrhosis. Preliminary results were reported at the 86th Annual Meeting of the Deutsche Gesellschaft für Innere Medizin     

The influence of sex on pharmacokinetics

Biologic differences exist between men and women that can result in differences in responses to drugs. Both pharmacokinetic and pharmacodynamic differences between the sexes exist, with more data on pharmacokinetic differences. On average, men are larger than women. Body size differences results in larger distribution volumes and faster total clearance of most medications in men compared to women. Greater body fat in women (until older ages) may increase distribution volumes for lipophilic drugs in women. Total drug absorption does not appear to be significantly affected by sex although absorption rates may be slightly slower in women. Bioavailability after oral drug dosing, for CYP3A substrates in particular, may be somewhat higher in women compared to men. Bioavailability after transdermal drug administration does not appear to be significantly affected by gender; nor does protein binding. Renal processes of glomerular filtration, tubular secretion, and tubular reabsorption appear to be faster in men compared to women whether considered on a mg/kg basis or total body weight basis. Algorithms to estimate glomerular filtration rate incorporate sex as a factor; some also include weight. For hepatic processes, drugs metabolized by Phase I metabolism (oxidation, reduction, and hydrolysis via cytochrome P450's 1A, 2D6, 2E1), Phase II conjugative metabolism (glucuronidation, conjugation, glucuronyltransferases, methyltransferases, dehydrogenases) and by combined oxidative and conjugation processes are usually cleared faster in men compared to women (mg/kg basis). Metabolism by CYP2C9, CYP2C19, and N-acetyltransferase, appear to be similar in men and women (mg/kg). Clearance of p-glycoprotein substrates appear to be similar in men and women. In contrast, total clearance of a number of CYP3A substrates appear to be mildly or moderately faster (mg/kg) in women compared to men. The clinical significance of reported differences warrants consideration. Clearance reported on a per kg basis directly addresses organ or enzyme clearance. The difference in size between men and women means translating these results to clinical dosage rates should include an adjustment for body size. Unfortunately, this is not standard. Reports of sex differences that persist after considering weight may warrant further dosage adjustments. In addition, investigations are often performed in healthy fasting individuals yet medications are prescribed to patients with confounding influences of disease, co-medications, diet, and social habits. The relative role of sex on pharmacokinetics as compared to genetics, age, disease, social habits and their potential interactions in the clinical setting is not yet fully known but should be routinely considered and further studied.     

贝那普利对氨氯地平药代动力学的影响

目的：比较受试者口服复方贝那普利（含盐酸贝那普利10mg和苯磺酸氨氯地平5mg）和氨氯地平（5mg）后体内氨氯地平的药代动力学特征，研究氨氯地平和贝那普利之间的相互作用。方法：采用两制剂、两周期随机交叉试验设计，12名男性健康受试者自身对照，口服复方贝那普利或氨氯地平。应用LC／MS／MS方法测定氨氯地平的血药浓度，并采用WinNonLin软件计算药代动力学参数。结果：复方和单方制剂中氨氯地平的平均药代动力学参数如下：Cmax分别为（2．6±0．6）、（2．8±0．7）μg／L，tmax分别为（5．8±1．3）、（5．3±1．0）h，AUC0-144分别为（99±39）、（109±26）μg·L^-1·h，t1/2分别为（37±6）、（44±12）h。各参数在两制剂间均无统计学意义。结论：贝那普利对氨氯地平在人体内的药动学过程没有显著影响。     

The influence of an experimental liver cirrhosis upon the metabolism of diazepam and imipramine hydrochloride in the rat

1. When either diazepam or imipramine hydrochloride was administered orally to rats with thioacetamide-induced hepatic cirrhosis, the biliary and faecal elimination of metabolites was significantly decreased compared with that in normal animals. However, renal excretion of metabolites of diazepam or imipramine was increased in the liver-damaged rats.

2. Experiments in vitro showed that liver homogenates from cirrhotic rats metabolized diazepam or imipramine hydrochloride in qualitatively and quantitatively similar ways to those from normal rats.

3. Clearance of radioactivity from the blood following i.v. administration of either diazepam or imipramine hydrochloride was prolonged in animals with experimental cirrhosis.     

The influence of an experimental liver cirrhosis upon the metabolism of diazepam and imipramine hydrochloride in the rat

When either diazepam or imipramine hydrochloride was administered orally to rats with thioacetamide-induced hepatic cirrhosis, the biliary and faecal elimination of metabolites was significantly decreased compared with that in normal animals. However, renal excretion of metabolites of diazepam or imipramine was increased in the liver-damaged rats. Experiments in vitro showed that liver homogenates from cirrhotic rats metabolized diazepam or imipramine hydrochloride in qualitatively and quantitatively similar ways to those from normal rats. Clearance of radioactivity from the blood following i.v. administration of either diazepam or imipramine hydrochloride was prolonged in animals with experimental cirrhosis.     

Influence of cirrhosis on lamotrigine pharmacokinetics

AIMS: Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. METHODS: Thirty-six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. RESULTS: The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child-Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child-Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half-life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). CONCLUSIONS: Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child-Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.     

The effects of hepatic impairment on the pharmacokinetics of doxazosin

The pharmacokinetics of doxazosin was determined in an open-label study of 12 male volunteers with hepatic impairment (stable alcoholic cirrhosis) and 12 healthy male volunteers. Participants (fasting) received a single 2 mg doxazosin tablet, and blood samples were collected over a 120-hour period. Safety assessments included laboratory and vital sign (blood pressure, pulse rate, and ECGs) measurements and recording of all reported adverse events. The mean peak plasma concentrations were 10.8 ng/mL and 12.3 ng/mL for the subjects with hepatic impairment and healthy subjects, respectively. The corresponding mean area under the plasma concentration-time curve values were 246 and 172 ng.h/mL, a 43% increase in exposure in the subjects with hepatic impairment (p = 0.02). Although the apparent oral clearance was reduced by 30% in men with hepatic impairment compared with healthy subjects (p = 0.02), the elimination halflife was not significantly changed (24 vs. 22 hours, respectively). Laboratory test results, vital signs, and the incidence of adverse events were similar for the two treatment groups. These findings indicate that the recommended dosing regimen for doxazosin is appropriate for patients with clinically mild to moderate hepatic impairment.