Combined recirculation of the rat liver and kidney: Studies with enalapril and enalaprilat

Combined recirculation of the rat liver (L) and kidney (IPK) at 10 ml min^–1 per organ (LK) was developed to examine the hepatorenal handling of the precursor-metabolite pair: [¹⁴C]-enalapril and [³H]enalaprilat. Loading doses followed by constant infusion of [¹⁴C]enalapril and preformed [³H]enalaprilat to the reservoirs of the IPK or the LK preparation was used to achieve steady stale conditions. In both organs, enalapril was mostly metabolized to its dicarboxylic acid metabolite, enalaprilat, which was excreted unchanged. At steady state, the fractional excretion for [¹⁴C]enalapril (FE=0.45 to 0.48) and preformed [³H]enalaprilat (FE{pmi}=1.1) were constant and similar for both the IPK and LK. The additivity of clearance was demonstrated in the LK preparation, namely, the total clearance of enalapril was the sum of its hepatic and renal clearances. However, the apparent fractional excretion for fanned [¹⁴C]enalaprilat, FE{mi} and the apparent urinary clearance were time-dependent and higher than the corresponding values for preformed [³H]enalaprilat in both the IPK and LK. The FE{mi} and urinary clearance values further differed between the IPK and LK. Biliary clearance of formed vs. preformed enalaprilat displayed the same discrepant trends as observed for FE{mi} vs. FE{pmi} for the LK. These observations on the time-dependent and variable excretory clearance (urinary or biliary) of the formed metabolite vs. the constant, and much reduced, excretory clearance of the preformed metabolite are due to dual contributions to formed metabolite excretion: the nascently formed, intracellular metabolite which immediately underwent excretion and the formed metabolite which reentered the circulation, behaved as a preformed species. When data for the IPK and LK preparations were modeled with a physiological model with parameters previously reported for the L and IPK, all data, including metabolite excretory clearances, were well predicted. Model simulations revealed that the apparent FE{mi} differed between the LK and IPK preparations when the liver was present as an additional metabolite formation organ; the apparent excretory (urinary orGlossary k⁰ infusion rate into the reservoir - C_R reservoir concentration - C_Out,k and C_Out,L venous concentrations for the kidney and liver - C_p,k and c_P,L concentrations in renal and hepatic plasma, respectively - C_k and C_L concentrations in kidney and liver tissue, respectively - C_U and C_Bile concentrations in urine and bile, respectively - CL _b ⁱⁿ andCL _b ^ef influx and efflux clearances, respectively, at the basolateral membrane of the renal tubular cell - C _l ⁱⁿ and CL _l ^ef influx and efflux clearances, respectively, at the luminal membrane of the renal tubular cell - CL _int,K ^m renal metabolic intrinsic clearance of the drug - CL _d ⁱⁿ and CL _d ^ef influx and efflux clearances, respectively, at the sinusoidal membrane - CL _int ^m,L hepatic metabolic intrinsic clearance of the drug - CL _int,L ^b biliary intrinsic clearance - V_R plasma reservoir volume - V_P,K and V_P,L plasma volumes of the kidney and liver, respectively - V_K and V_L tissue volumes of the kidney and liver, respectively - V_U and V_Bile volumes of urine and bile, respectively - Q_K and Q_L total renal and hepatic plasma flow rates, respectively - GFR glomerular filtration rate - Q_U and Q_Bile urine and bile flow rates, respectively - f_P, f_K, and f_L unbound fractions in plasma and kidney and liver tissue, respectively This work was supported by the Medical Research Council of Canada. I. A. M. de Lannoy was a recipient of the Ontario Graduate Scholarship from the Ontario Ministry of Health; K. S. Pang was a recipient of the Faculty Development Award, Medical Research Council.     

双室模型药物静脉输注方案的数学探讨

静脉输注是临床上广泛用于抢救危重病例的一种有效的给药方法,缺点是开始输注时血药浓度偏低。为了使血药浓度迅即达到临床治疗的最佳有效血药浓度,有一种简便易行的方法是在开始时立即静注一个底药剂量,同时以恒定速度进行静脉输注,以维持该血药浓度。这种静脉输注方案的关键问题在于采用何种底药剂量和以何种速度静脉输注。对于双室模型的药物,1971年及1972年Boyes及Mitenko先后提出了两种不同的静脉输注方案。本文用组合曲线求组合常数的方法推导出了介于上述两种方案之间的一种新的静脉输注方案,给出了这种新方案的“血药浓度一时间”曲线公式,并从理论上证明这种方案的优越性。     

Disposition kinetics in dogs of diethyldithiocarbamate,a metabolite of disulfiram

Following the intravenous infusion of sodium diethyldithiocarbamate to dogs, the disposition kinetics of diethyldithiocarbamate (DDC), a metabolite of disulfiram, were assessed. Approximately 27% of the administered dose was S-methylated, this process exhibiting a mean first-order rate constant of 0. 0569 min^–1 (t_1/2=12.2 min), while the remainder was eliminated by other routes having a rate constant of 0.148 min^–1 (t_1/2=4.68 min). The methyl diethyldithiocarbamate (MeDDC) formed from DDC showed an elimination rate constant of 0.0141 min^–1 (t_1/2=49.2 min). These observations are discussed in the light of previous investigations where the presence of MeDDC has rarely been sought or reported. A few comparisons with prior studies, in which DDC or disulfiram was administered, are made by retrospective kinetic evaluation of published data. The results are discussed in relation to the duration of action of disulfiram in man.Glossary A plasma concentration intercept at the cessation of infusion (mass/volume) - A _T simplifying constant (mass/volume/time) - AUC _M area under the plasma concentration-time curve for MeDDC (mass × time/volume) - b time variable; equalst during infusion, equalsT after the cessation of infusion - B plasma concentration intercept at the cessation of infusion (mass/volume) - B _T simplifying constant (mass/volume/time) - C _D plasma concentration of DDC at any timet (mass/volume) - C _M plasma concentration of MeDDC, expressed as DDC, at any timet (mass/volume) - C _T plasma concentration of total DDC, expressed as DDC, at any timet;C _T=C_D+C_M (mass/volume) - C _t plasma concentration of total DDC, expressed as DDC, at any timet (mass/volume) - Cl _D total body clearance of DDC (volume/time) - Cl _M total body clearance of MeDDC (volume/time) - DDC diethyldithiocarbamate - f fraction of DDC that is methylated;f=K _DM/K _D - K _A apparent first-order rate constant (reciprocal time) - K _B apparent first-order rate constant (reciprocal time) - K _D apparent first-order rate constant for the elimination of DDC by all routes (reciprocal time) - K _M apparent first-order rate constant for the elimination of MeDDC by all routes (reciprocal time) - K _DE apparent first-order rate constant for the elimination of DDC by all routes except methylation (reciprocal time) - K _DM apparent first-order rate constant for theS-methylation of DDC (reciprocal time) - MeDDC methyl diethyldithiocarbamate - NaDDC sodium diethyldithiocarbamate (trihydrate) - Q zero-order infusion rate constant (mass/time) - Q ₁ zero-order infusion rate constant for the faster of two consecutive infusions (mass/time) - Q ₂ zero-order infusion rate constant for the slower of two consecutive infusions (mass/time) - t elapsed time since dosing (e.g., infusion) commenced - t elapsed time since the cessation of infusion - T duration of infusion (time) - T ₁ duration of the faster of two consecutive infusions (time) - T ₂ total duration of infusion when two consecutive infusions are administered (time) - V _D apparent volume of distribution of DDC - V _M apparent volume of distribution of MeDDC This work was supported by the Atkinson Charitable Foundation (Toronto, Ontario, Canada) and the Non-Medical Use of Drugs Directorate, Health and Welfare Canada (Grant No. 1212-5-206).     

Influence of viability on bromosulfophthalein uptake by isolated hepatocytes

Summary The initial rates of BSP uptake by isolated hepatocytes were compared in cells of good and poor viability. Cells with impaired viability were obtained by ageing or by accident also in fresh preparations. Viability was judged by trypan blue stainability, membrane potential and respiratory parameters indicative for energy state, substrate supply and plasma membrane permeability changes. It was found that concomitant with impaired viability there was a decline of uptake rates at low and an increase at high BSP concentrations with a crossover point at 10 M as manifest in an increase of K _m and V. Simultaneously, the affinity and size of the membrane bound fraction decreases. The results give kinetic support to the supposition that it is the decreased uptake from plasma to liver that is responsible for the prolonged plasma retention times in the liver function test of patients with impaired hepatobiliary function.Abbreviations BSP Bromosulfophthalein - CCP Carbonylcyanide m-chlorophenylhydrazone A preliminary report was given on the Spring Meeting of the German Pharmacological Society at Mainz, March 23–26, 1976 [Schwenk, M., Burr, R., Pfaff, E.: Naunyn-Schmiedeberg's Arch. Pharmacol. 293, R48 (1976)].This study was supported by the Deutsche Forschungsgemeinschaft. The authors wish to thank Mrs. Sylvia Kasperek for skilful technical assistance.     

Application of the Loo-Riegelman absorption method

The Loo-Riegelman absorption method provides the correct A/V₁ value and the correct rate constant k_a (if absorption is first order), whether metabolism occurs in compartment 1 only, compartment 2 only, or both compartments 1 and 2 of the two-compartment open model. In cases where there is metabolism in compartment 2, the disposition parameters estimated from intravenous data are only apparent and not the real values. The correct A/V₁ and k_a values are obtained, however, only under conditions not hithertofore specified. These conditions are that there must be essentially no bias in the disposition parameters k₁₂, k₂₁, and k_el. and in the C₀ value estimated from the intravenous data, and that in the oral study a large number of interpolated plasma concentrations, as well as the observed plasma concentrations, must be used, especially for drugs with long half-lives. It is shown that application of the Guggenheim method to the initial A₁ V₁, tvalues frequently provides a better method of estimating A/V₁ and k_a than the classical method. If biased disposition parameters are used in application of the Loo-Riegelman method to oral data, then essentially the correct value of k_a will be estimated, but the estimate of A/V₁ will be approximately equal to the true value of A/V₁ multiplied by the ratio of the biased C₀ value (obtained in fitting the intravenous data) to the true C₀ value of the intravenous data. The above indicates that intravenous data should be fitted by computer until there are no systematic deviations or trends and as small a sum of squared deviations as possible is obtained. The oral data should be fitted by spline or Akima methods, or similar procedures, to produce a function which passes through each observed plasma concentration and at the same time provides a large number of interpolated concentration data.Partly supported by Public Health Service Grant 5-P11-GM15559.     

The influence of variable gastric emptying and intestinal transit rates on the plasma level curve of cimetidine; an explanation for the double peak phenomenon

A physiological flow model is presented to account for plasma level double peaks based on cyclical gastric emptying and intestinal motility in the fasted state. Central to the model is the assumption that gastric emptying and intestinal transit rates will vary directly with the strength of the contractile activity characteristic of the fasted state motility cycle. Simulated curves clearly indicate that variable gastric emptying rates can result in variable absorption rates from the gastrointestinal tract and double peaks in the plasma level curves of cimetidine. Vital to the occurrence of double peaks are (i) dosing time relative to phasic activity, (ii) variability in flow out of the stomach, and (iii) a small emptying rate constant Q_s/V_s, for a period of time within the first hour after administration. Variability in intestinal flow rates alone does not cause a double peak in the plasma level curve. Results of the simulations, as well as experimental results, can be categorized according to the shapes of the plasma level curves into four types: type A, C_pmax(1) pmax(2); type B, single peak; type C, C_pmax(1)>C_pmax(2); type D, C_pmax(1)=C_pmax(2). Assuming that the experimental results were obtained from fasted subjects, with the time of dose administration being a random variable, the frequency of the experimental curves having shape A, B, C, or D correlates extremely well with theoretical predictions. It is concluded that variable gastric emptying rates due to the motility cycle can account for plasma level double peaks. Furthermore, variable gastric emptying rates combined with the short plasma elimination half-life and poor gastric absorption of cimetidine can be the cause of the frequently observed plasma level double peaks.Notation A _s Amount of drug in the stomach - A _d Amount of drug in the duodenum - A _j Amount of drug in the jejunum - A _i Amount of drug in the ileum - A _p Amount of drug in the plasma - A _t Amount of drug in the peripheral compartment - Q _s Flow rate exiting the stomach - Q _d Flow rate exiting the duodenum - Q _j Flow rate exiting the jejunum - Q _i Flow rate exiting the ileum - V _s Volume of stomach contents - V _d Volume of duodenal contents - V _j Volume of jejunal contents - V _i Volume of ileal contents - V _p Volume of distribution - V _s ^o Initial volume of stomach contents - K _as Absorption rate constant of cimetidine from the stomach - K _ad Absorption rate constant of cimetidine from the duodenum - K _aj Absorption rate constant of cimetidine from the jejunum - K _ai Absorption rate constant of cimetidine from the ileum - K ₁₂ Distribution rate constant of cimetidine from plasma to tissue - K ₂₁ Distribution rate constant of cimetidine from tissue to plasma - K ₁₀ Elimination rate constant of cimetidine from the plasma - I Input of drug into the plasma from the gastrointestinal tract - DER Emptying rate of the drug from the stomach into the duodenum - C _pmax(1) First maximum drug concentration in the plasma - C _pmax(2) Second maximum drug concentration in the plasma - t _max(1) Time of first maximum drug concentration in the plasma - t _max(2) Time of second maximum drug concentration in the plasma This work was supported by the Smith Kline Beckman Corporation and the American Foundation for Pharmaceutical Education.     

Nonlinear elimination and hepatic concentration of conjugation- metabolite of valproate in guinea-pigs

The plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea-pigs placed on various (0.08-9 μmol ml^?1 = 11–1303 μg ml^?1) steady-state plasma concentrations (C_ss) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 μmol ml^?1 (88 μg ml^?1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (V_max) and the Michaelis-Menten constant (K_m) for the primary (V_maxl, K_ml) and the secondary (V_max2, K_m2) pathways were V_maxl = 1.52 μmol min ^?1kg^?1, K_ml = 0.15 μmol ml^?1, V_max2 = 24.98 μmol min ^?1 kg^?1 and K_m2 = 11.70 μmol ml^?1, respectively. The K_ml value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose-dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (f_u), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The K_m value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the K_ml value. These results implied that the primary metabolic parameters may describe the conjugation pathway which is nonlinear within the clinical therapeutic concentration range.     

Effect of uranyl nitrate-induced acute renal failure on the pharmacokinetics of sulfobromophthalein in rats

The effect of acute renal failure (ARF) on the pharmacokinetics of sulfobromophthalein (BSP) was investigated in order to elucidate if renal failure modifies the hepatic metabolism of drugs. ARF was induced by intravenous (iv) injection of uranyl nitrate (UN) to rats (5 mg/kg) five days before the experiment. Area under the plasma concentration-time curve (AUC) of BSP after portal vein (pv) injection increased by 2-fold and total body clearance (CL _t) decreased one half (p<0.01) in UN-induced ARF (UN-ARF) rats compared to the control rats. But the plasma disappearance of BSP afteriv injection did not differ significantly between control and UN-ARF rats. Since BSP is excretedvia the liver,CL _t representd the approximate hepatic clearance of BSP. Therefore, the decrease inCL _t represents a decrease in hepatic intrinsic clearance (CL _int) for BSP since plasma free fraction (f _p) of BSP was not affected by UN-ARF. The content of hepatic cytoplasmic Y-protein, which catalyzes BSP-glutathione conjugation and limits the transfer of BSP from blood to bile, increased significantly (p<0.01), however its binding activity (BA) for BSP was decreased significantly (p<0.01) by UN-ARF. The decrease inCL _int might have some correlation with the changed characteristics of hepatic Y-protein, specifically its decreased BA for BSP.     

Butylbiguanide concentration in plasma,liver, and intestine after intravenous and oral administration to man

Summary 50 mg¹⁴C-Butylbiguanide was administered intravenously to 4 diabetic patients and 100 mg¹⁴C-butylbiguanide orally to 5 further diabetics. The concentrations of the drug in plasma, intestinal fluid, intestinal epithelium and liver tissue were determined and the renal excretion of the biguanide measured. Irregularities in the plasma concentration curve were observed which appeared as systematic deviations from the ideal curve of a biexponential function. Because these deviations occurred only in the middle phase of the plasma concentration curve, it was nevertheless possible to calculate the pharmacokinetic parameters of butylbiguanide by use of a two-compartment open model. The principal pharmacokinetic parameters were determined according to this model after intravenous dosing and the following mean values were obtained:t _{1/2 ()}=4.6 h (=0.15 h^–1),C _P ⁰ =0.85µg/ml,V _D =218 l,V _T =157 l,V _P =62 l,k ₁₂=0.69 h^–1,k ₂₁=0.44 h^–1,k _el =0.54 h^–1. Within 48 h after administration, an average of 72.4% of the intravenous and 74.4% of the oral dose had been excreted in the urine. Total clearance (Cl _tot) averaged 536 ml/min and renal clearance (Cl _ren) 393 ml/min. High concentrations of butylbiguanide were observed in the intestinal fluid (100–700 mg/ml) 20–40 min after oral administration. It was found that the drug accumulates in intestinal fluid, intestinal epithelium and liver tissue, and that it is secreted into the intestinal lumen. The concentrations of butylbiguanide in intestinal and liver tissue were 10–46 times higher than in plasma. The secretion of biguanide into the intestinal lumen may occur via the bile or the intestinal mucosa, but there is no evidence of significant biliary excretion of butylbiguanide.     

Formed and preformed metabolite excretion clearances in liver,a metabolite formation organ: Studies on enalapril and enalaprilat in the single-pass and recirculating perfused rat liver

Single-pass and recirculating rat liver perfusion studies were conducted with [¹⁴C]enalapril and [³H] enalaprilat, a precursor-product pair, and the data were modeled according to a physiological model to compare the different biliary clearances for the solely formed metabolite, [¹⁴C]enalaprilat, with that of preformed [³H]enalaprilat. With single-pass perfusion, the apparent extraction ratio (or biliary clearance) of formed [¹⁴C]enalaprilat was 15-fold the extraction ratio of preformed [³H] enalaprilat, an observation attributed to the presence of a barrier for cellular entry of the metabolite. Upon recirculation of bolus doses of [¹⁴C]enalapril and [³H]enalaprilat, the biliary clearance, estimated conventionally as metabolite excretion rate/midtime metabolite concentration, for formed [¹⁴C]enalaprilat was again 10-to 15-fold higher than the biliary clearance for preformed [³H]enalaprilat, but this decayed with perfusion time and gradually approached values for preformed [³H]enalaprilat. The decreasing biliary clearance of formed enalaprilat with recirculation was explained by the dual contribution of the circulating and intrahepatic metabolite (formed from circulating drug) to excretion. Physiological modeling predicted (i) an influx barrier (from blood to cell) at the sinusoidal membrane as the rate-limiting process in the overall removal of enalaprilat, (ii) a 15-fold greater extraction ratio or biliary clearance for formed [¹⁴C]enalaprilat over [³H]enalaprilat during single-pass perfusion, and (iii) the time-dependent and declining behaviour of the biliary clearance for formed [¹⁴C]enalaprilat during recirculation of the medium. In the absence of a direct knowledge of eliminating organs in vivo, this variable pattern for excretory clearance of the formed metabolite within the organ is indicative of a metabolite formation organ.Glossary C _R denotes the reservoir concentration - C _In andC _Out,L respectively, denote the input and output concentrations. - Q _L is the total hepatic plasma flow rate. - Q _Bile is the bile flow rate - f _p and f_L denote the unbound fractions in plasma and liver tissue, respectively - C_p is the concentration in renal plasma; C_L is the concentration in liver; - C _Bile is the concentration in bile. - v _R,V _p,V _L, andV _Bile denote the reservoir plasma, hepatic plasma, tissue, and bile volumes, respectively - CL _d ⁱⁿ andCL _d ^ef denote the influx and efflux clearances, respectively - CL _int,L ^m ,L represents the hepatic metabolic intrinsic clearance of the drug - CL _int,L ^b L denotes the biliary intrinsic clearance This work was supported by the Medical Research Council of Canada. I. A. M. de Lannoy was a recipient of the Ontario Graduate Fellowship from the Ontario Ministry of Health; K. S. Pang was a recipient of the Faculty Development Award, Medical Research Council, Canada.     

Human pharmacokinetics of tolfenamic acid,a new anti-inflammatory agent

Summary The pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent was studied in six healthy volunteers after an intravenous dose of 100 mg and oral doses of 100, 200, 400 and 800 mg. The disposition of intravenous tolfenamic acid could be described by two-compartment open model, with a central compartment volume (V_dc) of 5.6±0.31 (mean±SE), volume during -phase (V_d) of 31±21, and a total elimination rate constant (k₁₀) 1.6±0.1 h^–1. The terminal elimination half-life was 2.5±0.6 h and the total plasma clearance 155±15 ml/min. The elimination occured principally by extrarenal mechanisms, the recovery of unchanged drug together with is glucuronide in urine averaging only 8.8% of the intravenous dose. The binding of tolfenamic acid to plasma proteins averaged 99.7%. The gastrointestinal absorption had a mean half-life of 1.7±0.1 h. Based on comparison of areas under the plasma concentration time-curves after intravenous and oral administration, the biovailability of tolfenamic acid capsules averaged 60%. The rate and extent of absorption and the rate of elimination of tolfenamic acid were independent of dose.     

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 quinidine and three of its metabolites in man

Disposition parameters of quinidine and three of its metabolites, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9±(SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32±0.06 mg/L; quinidine N-oxide, 0.28±0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13±0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89±0.50 mg/L; 3-hydroxy quinidine, 0.83±0.36 mg/L; quinidine N-oxide, 0.40±0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38±0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves after both i.v. infusion and multiple oral doses. Mean (±SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: V ₁ ,0.37±0.09 L/kg; ₁,0.094±0.009 min ^–1; ₂, 0.0015±0.0002 min^–1; EX2, 0.013±0.002 min^–1;clearance (Cl_Q),3.86±0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (±SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant k_mf,0.0012±0.0005 min ^–1,volume of distribution, V_m,0.99±0.47 L/kg; and elimination rate constant, k_mu 0.0030±0.0002 min ^–1.Quinidine N-oxide: k_mf,0.00012±0.00003 min ^–1; V_m,0.068±0.020 L/kg; and k_mu,0.0063±0.0008 min ^–1.Quinidine 10,11-dihydrodiol: k_mf,0.0003±0.0001 min ^–1; V_m,0.43±0.29 L/kg; and k_mu,0.0059±0.0010 min ^–1.Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.This work was supported by funds from the grants GM 26691 and GM 28072 from the National Institute of General Medical Sciences, NIH. A. Rakhit was the recipient of a Training Grant Traineeship from NIH. T. W. Guentert is grateful for support from the Swiss National Science Foundation.Professor Sidney Riegelman. deceased April 4, 1981.     

Analysis of nonlinear tissue distribution of quinidine in rats by physiologically based pharmacokinetics

The nonlinear tissue distribution of quinidine in rats was investigated by a physiologically based pharmacokinetic model. Serum protein binding of quinidine showed a nonlinearity over thein vivo plasma concentration range. The blood-to-plasma concentration ratio (C _b/C _p) of quinidine also showed a concentration dependence. The steady-state volume of distribution (V _ss) determined over the plasma concentration range from 0.5 to 10 g/ml was 6.0 ±0.45 L/kg. The tissue-to-plasma partition coefficient (Kp) of muscle, skin, liver, lung, and gastrointestinal tract (GI) showed a nonlinearity over thein vivo plasma concentration range of quinidine, suggesting saturable tissue binding. The concentration of quinidine in several tissues and plasma was predicted by a physiologically based pharmacokinetic model usingin vitro plasma protein binding and theC _b/C _p of quinidine. The tissue binding parameters were estimated fromin vivo Kp values. The predicted concentration curves of quinidine in each tissue and in plasma showed good agreement with the observed values.This study was supported by a grant-in-aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.     

Dose-effect curves and relative biophasic drug levels: Elucidation of these concepts and the illustration of their use for the determination of bioavailability,rate of absorption,and time course of pharmacological response

The theoretical basis for the development of dose-effect curves, linear dynamic models, and relative biophasic drug levels as derived from pharmacological response intensity is presented. The presentation is kept sufficiently rigorous to demonstrate the theoretical soundness of the concepts, yet each concept is clearly explained and related to physical experimental variables so as to be physically meaningful. The use of these concepts for the determination of bioavailability, rate of absorption, and time course of drug action is demonstrated.Notation A _i amplitude coefficients for impulse response equations - BDA biophasic drug availability - CA cumulative amount of drug absorbed - C _p concentration of drug in the plasma - D magnitude of impulse input - D relative biophasic drug level - f(I) relative biophasic drug level (7) - G(s) transfer function for system - I intensity of pharmacological response - m _i time constant for impulse response equation - n number of compartments in the system - PDA physiological drug availability - Q _B biophasic drug level - RBA relative biophasic drug availability - s Laplace transform variable - SDA systemic drug availability - STD. standard dose - t time, the independent variable - u(t) unit impulse input - V _D volume of distribution - U(s) Laplace transform of unit impulse input - _t a function of time, defined by equation 1     

DOSE-DEPENDENT DISTRIBUTION VOLUMES OF TOTAL AND UNBOUND VALPROATE IN GUINEA-PIGS: CONSEQUENCE OF NON-LINEAR PLASMA PROTEIN BINDING

The response of steady-state distribution volume (V_dss for total and V_dssu for unbound drug) of valproate (VPA) to dose-dependent plasma protein binding was studied in guinea-pigs. Various steady-state plasma concentrations of VPA were achieved by intravenous constant infusion. The concentrations of VPA in plasma (C_ss for total and C_uss for unbound drug) and various tissues (C_T) were determined. The V_dss and the V_dssu were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction (f_u) of VPA increased significantly with dose. The V_dss was significantly increased with, while the V_dssu was significantly decreased against the increasing dose. The increase in V_dss with dose indicated an increase in tissue-to-plasma concentration ratio, which may be attributed to the increase in distribution of unbound drug from plasma to tissues subsequent to non-linear plasma protein binding. The decrease in V_dssu against the increasing dose indicated a decrease in tissue-to-unbound plasma concentration ratio, which suggests that the extravascular distribution of unbound VPA might be capacity limited and the tissue binding of VPA negligible.     

Salvianolic acid B as a substrate and weak catechol-O-methyltransferase inhibitor in rats

Abstract

1.?The aim of this study was to investigate the biotransformation of salvianolic acid B (SAB) by catechol-O-methyltransferase (COMT) and its interaction with levodopa (l-DOPA) methylation in rats.

2.?The enzyme kinetics of SAB were studied after incubation with rat COMT. The in vivo SAB and 3-monomethyl-SAB (3-MMS) levels were determined after a single dose of tolcapone with or without SAB administration. For l-DOPA, the effect of SAB inhibition on l-DOPA methylation was studied in vitro. The l-DOPA and 3-O-methyldopa (3-OMD) levels were determined after single and multiple doses of SAB with or without l-DOPA administration.

3.?After incubation, we found that SAB was methylated mainly by rat liver and kidney COMT. Tolcapone strongly inhibited the formation of 3-MMS in vitro and in vivo, without any change in the plasma concentration of SAB. Moreover, tolcapone significantly increased the cumulative bile excretion of SAB from 3% to 40% in the rat. SAB inhibited the methylation of l-DOPA with an IC₅₀ value of 2.08?μM in vitro. In vivo, a single intravenous dose of SAB decreased the plasma concentration of 3-OMD, with no obvious effect on the pharmacokinetics of l-DOPA. Multiple doses of SAB given to rats also decreased the plasma concentration of 3-OMD, while SAB increased the plasma concentration of l-DOPA.     

Two-compartment dispersion model for analysis of organ perfusion system of drugs by fast inverse laplace transform (FILT)

A dispersion model developed in Chromatographic theory is applied to the analysis of the elution profile in the liver perfusion system of experimental animals. The equation for the dispersion model with the linear nonequilibrium partition between the perfusate and an organ tissue is derived in the Laplace-transformed form, and the fast inverse Laplace transform (FILT) is introduced to the pharmacokinetic field for the manipulation of the transformed equation. By the analysis of the nonlinear least squares method associated with FILT, this model (two-compartment dispersion model) is compared to the model with equilibrium partition between the perfusate and the liver tissue (one-compartment dispersion model) for the outflow curves of ampicillin and oxacillin from the rat liver. The model estimation by Akaike's information criterion (AIC) suggests that the two-compartment dispersion model is more proper than the one-compartment dispersion model to mathematically describe the local disposition of these drugs in the perfusion system. The blood space in the liver, V_B, and the dispersion number D_N are estimated at 1.30 ml (±0.23 SD) and 0.051 (±0.023 SD), respectively, both of which are independent of the drugs. The efficiency number, R_N, of ampicillin is 0.044 (±0.049 SD) which is significantly smaller than 0.704 (±0.101 SD) of oxacillin. The parameters in the two-compartment dispersion model are correlated to the recovery ratio, F_H, mean transit time, ¯t_H, and the relative variance, ²/¯t_H ², of the elution profile of drugs from the rat liver.Notation A Cross-sectional area of the blood space - C(t, z) Concentration of drug (one-compartment dispersion model) - C(s, z) Laplace transform of C(t, z) - C ₁(t, z) Concentration of drug in blood space (two-compartment dispersion model) - C ₂(t, z) Concentration of drug in the liver tissue (two-compartment dispersion model) - C ₁ (s, z) Laplace transform ofC ₁(t, z) - D Axial or longitudinal dispersion coefficient - D _c(=D· A ²) Corrected dispersion coefficient - D _N Dispersion number - f _I(t) Input function with respect tot - f_I(z) Input function with respect toz - F_I(s) Laplace transform of f_I(t) - f_s(t) System weight function with respect tot - f_s(z) System weight function with respect to z - F_H Recovery ratio - k Partition ratio (distribution ratio) - k₁₂, k₂₁ Forward and backward partition rate constant in the central elimination two-compartment dispersion model - k ₁₂ ^p ,k ₂₁ ^p Forward and backward partition rate constant in the peripheral elimination two-compartment dispersion model - k_e Elimination (or irreversible transfer) rate constant - k _e ^p Elimination rate constant in peripheral elimination model - K_H Distribution constant - L Length of blood space in liver - M Amount of drug injected - m Coefficient related to the injected amount - p_h Mass transfer coefficient from perfusate to hepatic tissue - Q Flow rate of perfusate - R_N Efficiency number - s Laplace variable - t Time - ¯ t_H Mean transit time - Linear flow velocity of the perfusate - V _B(= L·A) Blood volume (sum of the sinusoid volume and the space of Disse) - v_h Apparent volume of distribution - V _H Anatomical volume of liver tissue - z Axial coordinate in the liver - (t) Delta function - Volume ratio of the anatomical liver tissue to the blood space - ² Variance of transit time - ²/¯t _H ² Relative dispersion to transit time - Partial derivatives     

A pharmacokinetic slide rule for more accurate drug treatment

Summary A slide rule has been devised which is based on the general mathematical models of pharmacokinetics. It permits calculation of exact dosage regimens for individual patients from certain basic parameters. First, from the patient's renal clearance, the proportionality constant characterizing renal excretion of a certain drug (a) and its non-renal rate constant of elimination (k _nr), the rate constant of total elimination (k _e) can be calculated. Second, fromk _e, the apparent volume of distribution (V _d) and the desired final mean concentration of a drug (c), exact values can readily be obtained for the loading dose (D*) and the dosage schedule, which consists of the maintenance dose (D), the dosing intervals () and the infusion rate for intravenous administration. In addition the slide rule provides information about the rate at which c is reached ifD alone is administered at , and the fluctuation in the concentration around c to be anticipated during . By use of this calculation, the slide rule facilitates the decision whether a loading dose should be given, and what dosage schedule is best suited to the therapeutic problem. It is possible, therefore, to calculate exact dosage regimens for individual patients, even for those with excretory dysfunction. The slide rule should also help physicians to comprehend the nature and significance of pharmacokinetic mechanisms.     

Excretion of sulfobromophthalein in rats with iodomethane-induced depletion of hepatic glutathione

Summary Male urethane-anesthetized Wistar rats with biliary fistulas were infused for 60 min i.v. with sulfobromophthalein (BSP) or BSP-glutathione conjugate (BSP-GSH) at 594 nmol/100 g/min. Thirty minutes prior to the start of the infusion, 20 mg/kg iodomethane, dissolved in olive oil, was given into the duodenum. The control received oil only. At the start of the infusion the hepatic concentration of GSH was 0.96±0.23 mg/g liver in the iodomethanetreated animals versus 1.93±0.13 mg/g liver in the control (P<0.001).When unconjugated BSP was infused, the excretion of total BSP (unconjugated plus conjugated) was markedly lower in the iodomethane-treated group than in the control. This difference was due solely to differences in biliary appearing conjugated BSP; the excretion of unconjugated BSP was identical in both groups. The different excretion patterns were paralleled by equal hepatic accumulation of total BSP in both groups. The ratio of unconjugated BSP/BSP-GSH in the liver was about twice as high after pretreatment with iodomethane than in the control group.When BSP-GSH instead of BSP was infused, the excretion rates of this dye were identical in both groups. The maximal transport capacity (T_m) was double that observed with infusion of unconjugated BSP in control animals. There is indirect evidence that BSP and BSP-GSH might have different excretion pathways.