Use of a Pharmacokinetic Model Incorporating Discontinuous Gastrointestinal Absorption to Examine the Occurrence of Double Peaks in Oral Concentration–Time Profiles

Double peaks in the plasma concentration–time profile following oral administration have been reported for several compounds. A pharmacokinetic model incorporating discontinuous absorption was developed to simulate concentration-time profiles with double peaks. The gastrointestinal (GI) tract was divided into N compartments, with absorption occurring only from the second and Nth compartments. A two-compartment model was used to describe systemic drug disposition. The effect of gastric emptying and GI transit rate constants (K _l and K _t, respectively), number of hypothetical gut compartments, and absorption rate constant at each site (K _a1, K _a2) on the time of occurrence of each peak (T _pl, T _p2), the theoretical fraction of the dose absorbed at each site ( ₁, ₂), and the contribution of the second site to systemic drug exposure (expressed as _2rel) were examined. Simulated concentration–time profiles demonstrated that T _p2 was determined by K _t and N, while T _p1 was determined by K _l and K _t. Changes in K _a1 and K _a2 had no effect on T _p1 or T _p2. ₁ , ₂, and _2rel were determined by K _al, K _a2, and K _t, and simulations indicated that a secondary peak in the concentration-time profile will be evident only when _2rel is substantial. In addition, concentration–time data for ranitidine and cimetidine, which displayed double peaks, were fit with the model. The present model described both data sets well, and realistic pharmacokinetic and physiologic parameters (absorption rate constants, systemic bio-availabilities, GI residence times) were obtained.     

Measurement of protein binding for drugs that are unstable in aqueous solution

Differential model equations were proposed to describe the dynamics of drug-macromolecule binding for drugs which are inherently unstable in solution. Equations relating to stable drugs comprise a specific case of the general model.To verify the model, binding parameters for the interaction of methyl diethyldi-thiocarbamate (MeDDC), a stable drug, and bovine serum albumin (BSA) were compared by using a rapid equilibrium dialysis system in its customary equilibrium mode and according to the dynamic model. No significant differences in the equilibrium association constant (K_a), the maximum molar bound concentration (C_b)_max, or their product were found. The dynamic model was then used to determine K_a and (C_b)_max for diethyldithiocarbamate (DDC), an unstable drug.The procedure does not require the prior measurement of a diffusion rate constant in the absence of BSA. Because experimentally measured data may be entered directly into the computer program (NONLIN) used to determine the binding parameters, statistically undesirable errors arising from the more common manipulation of such data prior to computation are minimized.     

Simple Methods for Estimation of Mean Residence Time and Steady-State Volume of Distribution from Continuous-Infusion Data

The following equations are derived for amount of drug in the body (x _bss), volume of distribution (v _ss), and mean residence time in the body (t _b) at steady state during a continuous constant rate infusion of drug. x _bss = R/c _ss0 [c _ss - c(t)]dt = R₀ [1 - c(t)/c _ss]dt v _ss = x _bss/c _ss = R/c ² _ss0 [c _ss - c(t)]dt = R/c _ss0 [1 - c(t)/c _ss]dt t _b = x _bss/R = v _ss/CL = 1/c _ss0 [c _ss - c(t)]dt = ₀ [1 - c(t)/c _ss]dt where c(t) drug concentration in the systemic circulation at time t following the start of a constant-rate infusion, c _ss steady-state systemic drug concentration, and R infusion rate. The equations are based on the assumption that the rate of drug elimination is proportional to the systemic drug concentration. The equations provide the basis for simple methods that are presented for estimating x _bss, v _ss, and t _b directly from experimental data. More general relationships are also derived for cases where the continuous infusion is preceded by other modes of administration, e.g., a bolus loading dose followed by a constant-rate infusion.     

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     

Effect of thiocarbamate derivatives on copper,zinc, and mercury distribution in rats and mice

Oral treatment of rats with tetramethylthiuram disulphide (TMTDS), 0.1% mixed in the food (corresponding to 20–30 mol daily) for one week, increased the brain levels of endogenous copper and zinc to 120% and 170%, respectively, of the control levels.Mice injected with HgCl₂ (2.5 mol/kg) were used to study further the effect of DDC (diethyldithiocarbamate), disulfiram, TMTDS or CS₂ on heavy metal distribution. The brain levels of Hg were significantly increased in mice given DDC or TMTDS. Disulfiram and CS₂ increased the brain levels marginally.Pregnant rats exposed to HgCl₂ (0.5 mol/kg) were also included in the studies. Treatment with DDC (0.5 mmol/kg) immediately after the mercury injection, increased the maternal brain concentration of mercury considerably, as measured after 24 and 78 h. The kidney levels were also increased. In the foetuses, the brain and liver levels were transiently increased after treatment with diethyldithiocarbamate.The observations support the hypothesis that the neurotoxicity of diethyldithiocarbamate and other thiocarbamates may be related to changes in heavy metal metabolism.     

Pharmacokinetics of sulfametopyrazine (Kelfizine W) effects of a single oral dose

Summary The pharmacokinetics of sulfametopyrazine were studied for seven days after a single oral dose of 2 g. in healthy volunteers in order to establish its chemotherapeutic value. — The appearance and disappearance of the drug in the plasma were evaluated both for compounds with a free amino group and for total sulphonamides. The half-life and absorption, distribution, elimination and excretion coefficients were calculated, as well as the concentrations in plasma water and interstitial fluid. The estimated drug concentrations in the urine agreed with those calculated from the excretion coefficients. — In all subjects at the end of the seventh day the concentrations in all body compartments of active compounds exceeded the minimum required for a therapeutic effect. The highest concentrations found in the urine were always significantly lower than the drug's basal solubility at pH 5, thus excluding any risk of crystalluria.Glossary of symbols total binding capacity of plasma proteins for SMP - Specific gravity of blood ( Bl), and interstitial fluid (IF) - minimum inhibitory concentration for bacterial growth. Evaluation of against E. coli or other pathogenic bacteria in a medium free of antagonists [29] - ratio of dose interval to half-life - dose interval - safety factor. Proportionality constant between andc _min for a therapeutic efficacy of 95 per cent - fraction of the administered drug absorbed from the depot (gastrointestinal tract etc.) - distribution coefficient with respect to the drug concentration in blood plasma (ml/g) - D* initial dose of the drug - D maintenance dose - M molecular weight of the drug (280) - G weight of subject (kg) - F area between time axis and concentration curve (plotted c' values) - t _50% apparent biological half-life - w ¹ water content of plasma (ml/ml) - p protein concentration of plasma (pBl), or interstitial fluid (pIF) (g/l) - c _IF concentration in the interstitial fluid - C ₀ concentration in plasma at zero time after i.v. administration - c ₁ ⁰ concentration in plasma after oral absorption extrapolated to zero time - c ₁ concentration in plasma water of the drug with free amino function - c _min minimum inhibitory concentration needed in plasma water (minimum therapeutic concentration) - k ₀₁ rate constant for absorption - k ₁ rate constant for absorption determined at timet; (similarlyk₂) - K total elimination coefficient - k _el rate constant for elimination - k _F rate constant for formation of metabolites - k _D excretion coefficient of SMP with free amino function - k _U coefficient of metabolite excretion - D ₀ quantity of SMP in the body at time zero - D _B quantity of SMP in the body at timet - D _U quantity of SMP excreted in the urine at timet - M _F quantity of metabolites formed at timet - M _B quantity of metabolites present in the body at timet - M _U quantity of metabolites excreted in the urine at timet - K dissociation constant for the sulphonamide-protein complex - notation for quantities related to drug concentrations in plasma, e.g. c (corresponding term without refer to plasma water)     

Effect of probenecid on the elimination and protein binding of ceftriaxone

Summary The kinetics and binding parameters of ceftriaxone have been characterized in eight normal subjects who received, in sequence, 1.0 g ceftriaxone and 1.0 g ceftriaxone together with 250 and 500 mg probenecid q.i.d.Probenecid increased the total systemic clearance (CL _S ^T ) from 0.244 to 0.312 ml/min/kg, whereas the terminal half-life (t _1/2() ^T ) fell from 8.1 to 6.5 h. In contrast, the renal clearance of free ceftriaxone (CL _R ^F ) was decreased from 2.09 to 1.67 ml/min/kg, confirming a small but significant contribution of tubular secretion to the renal elimination of ceftriaxone.The final value of CL _R ^F was attained with the lower dose probenecid, whereas the non-renal clearance of free ceftriaxone (CL _NR ^F ) fell progressively from 2.78 to 1.90 ml/min/kg with the increasing probenecid dose. The total decrease in the systemic clearance of free ceftriaxone (CL _S ^F ) after the higher dose of probenecid was about 30% (4.87 to 3.57 ml/min/kg).As a consequence of a decreased affinity constant (K_A), the average free fraction in plasma (f) was increased by 54% after the low dose and by 74% after the high dose of probenecid.The protein binding interaction between probenecid and ceftriaxone appears to be unique. The results are of limited clinical consequence for ceftriaxone but they emphasise the importance of evaluating the kinetics of the free drug when examining interactions involving probenecid.Abbreviations AUC^T, AUC^F plasma AUC of total and free (unbound) drug - CL _S ^T , CL _S ^F clearance: total systemic, free systemic - CL _O ^T , CL _R ^F total oral, free renal - CL _NR ^F free non-renal - V _Z ^T V _SS ^T apparent volume of distribution: terminal phase, total drug; corrected steady-state, total drug [14] - f average free fraction of drug in plasma - f_e fraction of dose excreted unchanged in urine - t _1/2() ^T terminal t_1/2: total drug - t _1/2() ^F free drug - K_A affinity constant - nP capacity constant - C _av ^ss steady-state concentration in plasma during multiple dosing - C_B bound concentration - C_F free (unbound) concentration     

The effect of duration of intravenous infusion on maximum and threshold blood concentrations for drugs exhibiting biexponential elimination kinetics

The relationships among peak blood concentration (C _max), the time (t _D ) during which blood concentrations are maintained above the minimum effective concentration (C _min), and the duration of a constantrate intravenous infusion (T) of a drug exhibiting biexponential pharmacokinetics were simulated by digital computer using Newton iterative procedures. These simulations showed that, in contrast with our previous findings for drugs with monoexponential pharmacokinetics, the relationships are more complex due to the larger number of variables. Therefore, investigation of these relationships for biexponential drugs should be done on a drug by drug basis. Accordingly, meperidine and sulfamethoxazole were chosen as examples of drugs which exhibit biexponential kinetics and were used to determine what errors were involved in using the simpler guidelines for drugs which exhibit monoexponential kinetics as an approximation. These simulations showed the following. (a) The effect ofT onC _max may be adequately estimated by using the guidelines for monoexponential kinetics with the elimination half-life taken as provided that ₁ is 20 to 30 times ₁ and that theAUC of the distribution phase (i.e.,C _{1/ 1} comprises greater than about 20% of the totalAUC. (b) As with monoexponential drugs, it is possible to obtain a largert _D by infusing the dose compared to that obtained with a bolus, if the value ofC(0)/C _min>2.5. (c) Using the approximation of monoexponential pharmacokinetics to estimate the effect ofC ont _D will underestimate botht _D and the maximum infusion time, which will just attain theC _min unless theAUC of the distribution phase comprises only a very small proportion of the totalAUC. (d) The simulations with meperidine also showed that the nature of the relationship betweent _D andT varies depending on whetherC _min is maintained in the distribution phase or in both the distribution and elimination phases.     

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。     

A Combined Specific Target Site Binding and Pharmacokinetic Model to Explore the Non-linear Disposition of Draflazine

The capacity-limited high-affinity target site binding ofdraflazine to the nucleoside transporters located on the erythrocytes isa source of nonlinearity in the pharmacokinetics of the drug. Anattractive feature of draflazine is that the specific target sitebinding characteristics can be determined easily by simultaneouslymeasuring plasma and whole blood concentrations of the drug. Measureddrug concentrations following various infusion rates and infusiondurations were used to develop a model in which the interrelatedblood–plasma distribution, elimination, and specific target sitebinding of draflazine were incorporated simultaneously. The estimatedbinding (dissociation) constant K_d was0.57 ng/ml plasma and the maximal specific erythrocyte bindingcapacity was 163 ng/ml RBC. The maximal specific binding capacity to the tissues was estimated to be about 1 mg. The estimated volume of the central compartment(V_{plasma + tissue fluids}) was12.9 L and the total intrinsic CL was 645 ml/min. Aftervalidation, the model was used to further investigate the impact of thespecific high-affinity target site binding of draflazine on itsdisposition in plasma. The time required to reach steady-state plasmaconcentrations of draflazine decreased with an increasing infusion rate.Time profiles of the plasma concentrations were not alwaysrepresentative for the time profiles of the specific target site(RBC) occupancy of draflazine, but the t _1/2,z in plasma paralleled that of the drug at target sites. Theapparent V_d and the t _1/2,z decreased with increasing single doses whereas the total CLremained constant. The recovery of draflazine was also dosedependent and increased with increasing doses. Finally, the totalCL and apparent V_d of the first dose weregreater than those of the second dose of draflazine.     

Metabolic activation of halothane and its covalent binding to liver endoplasmic proteins in vitro

Summary Metyrapone inhibits the N-demethylation of aminopyrine and ethylmorphine in rat liver microsomes non-competitively with concentrations in the micromolar range, and competitively in the range of 10^–4 M. In the case of non-competitive inhibition, enzyme and inhibitor are present in similar amounts (mutual depletion system). Under these conditions Lineweaver-Burk kinetics do not apply, since the portion of inhibitor bound to the enzyme cannot be neglected. Inhibition of microsomal N-demethylating activity by increasing amounts of metyrapone and application of equations required for a mutual depletion system enable us to determine the following kinetic parameters: (1) the concentration of catalytically active and metyrapone sensitive centers (E _t ) of cytochrome P-450, (2) their turnover number (TN), and (3) the true dissociation constant of the enzyme inhibitor complex, K _i .—With aminopyrine as substrate and microsomes from phenobarbital (PB) pretreated rats, 1 mg of protein contains 4.7 nmoles of E _t , i.e. about 2.2 catalytically active sites per molecule of cytochrome P-450; TN=3.4 min^–1, and K _i =2.2·10^–6 M.The corresponding values for ethylmorphine and control rats are: E _t =3.1 nmolles per mg of protein (4.4 sites per molecule), TN=1.94 min^–1; K _i =2.37·10^–6M. PB-pretreated rats: E _t =7.3 nmoles per mg of protein (3.5 sites per molecule) TN=2.0 min^–1; K _i =2.3·10^–6 M.Comparing the values obtained for PB-pretreated rats and controls reveals that K _i and TN remain constant but E _t rises 2.3 fold. This is regarded to mean that PB pretreatment influences ethylmorphine N-demethylation only quantitatively but not qualitatively. The experiments described here provide data which improve the characterization of cytochrome P-450. They are derived from the overall rate of N-demethylation reactions in microsomes, independently from conventional spectrophotometric methods.     

Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity

Objective To study the effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia.Methods Nineteen patients received multiple doses of quetiapine (200 mg, twice daily) with or without co-administered erythromycin (500 mg, three times daily). Blood samples were collected at specified time intervals for determination of plasma concentrations of quetiapine and some of its metabolites.Results With erythromycin co-administration: for quetiapine, maximal plasma concentration (C _max), area under concentration–time curve of 0– h (AUC_0–) and terminal-phase elimination half-life time (t _1/2) increased 68, 129 and 92%, respectively, and clearance (CL) and terminal elimination rate constant (K _e) decreased 52% and 55%, respectively; for quetiapine sulfoxide (QTP-SF), C _max, AUC_0– and AUC ratio decreased 64, 23, and 70%, respectively, and t _1/2 increased 211%; for 7-hydroxy-quetiapine (QTP-H), K _e and AUC ratio decreased 61% and 45%, respectively, and t _1/2 increased 203%; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), C _max, AUC_0– and AUC ratio decreased 36, 40 and 71%, respectively.Conclusion Erythromycin has a noticeable effect on the metabolism of quetiapine. When quetiapine is co-administered with CYP3A inhibitors such as erythromycin, the dosing regimen should be modified according to quetiapine TDM.     

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     

溶液中药物稳定性的研究 Ⅲ.苯甲異噁唑青霉素纳水溶液的化学动力学研究

苯甲异噁唑青霉素钠在水溶液中的降解为伪一级反应,受H⁺,OH^-的催化,HPO₄^-的催化也相当剧烈.20℃时最稳定的pH值为6.54.在35℃,pH 1.5时,水溶液较青霉素G稳定9-10倍.37℃时在pH 6.5的一倍稀释的McIlvaine缓冲溶液中较青霉素G稳定1.5倍.0℃储藏十分稳定.文中给出了各种速度常数如K_{H^A-,KOH^A-,Ko,KHPO4^-的Arrhenius公式和稳定性的预测数值.}     

Effect of pregnancy on topiramate pharmacokinetics in rabbits

1. Pregnancy is associated with various physiological changes that may lead to significant alterations in the pharmacokinetic profiles of many drugs. The present study was designed to investigate the potential effects of pregnancy on the pharmacokinetics of topiramate (TPM) in the rabbit model.

2. Nineteen female New Zealand white rabbits (nine pregnant and 10 non-pregnant) were used in this study. Blood samples were collected from the animals just before receiving TPM orally at a dose of 20?mg/kg and then serially for up to 24?h. TPM plasma samples were analysed using a validated tandem mass spectrometric (LC-MS/MS) method.

3. The mean values of TPM pharmacokinetic parameters (t_1/2, T_max, AUC_0–∞, and CL/F) were significantly modified in pregnant rabbits as compared with non-pregnant group. Pregnancy significantly (P?<?0.05) increased TPM half-life (t_1/2), time to attain the maximum plasma concentration (T_max), and the area under TPM plasma concentration–time curve (AUC_0-∞) and decreased the drug’s oral clearance (CL/F) compared with non-pregnancy state in rabbits.

4. The present study demonstrates that pregnancy alters the pharmacokinetics of TPM in rabbits in late gestational period and considerable inter-animal variability was observed. The findings of the present study indicate that TPM CL/F is decreased during late pregnancy in the rabbit model.

     

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     

The effects of erythromycin on the absorption and disposition kinetics of theophylline

Summary The effects of erythromycin on the kinetics of theophylline were investigated in eight female patients with documented asthma in a crossover study. Theophylline pharmacokinetics were determined at steady state before and after one-week treatment with erythromycin stearate 250 mg given four times a day. Multiple serum samples were collected for 12 h after an aminophylline dose in the two drug treatment phases and assayed by high performance liquid chromatography. The resultant serum theophylline concentration-time data were analyzed by weighted, nonlinear regression analysis to obtain various pharmacokinetic parameters. In this study, the elimination half-live increased from 7.8±1.7 h on the control day to 9.5±1.4 h following treatment with the antibiotic (p<0.02). The estimated apparent volume of distribution for theophylline (V/F) was also observed to increase from 0.42±0.09 l/kg before treatment with erythromycin to 0.53±0.15 l/kg after antibiotic treatment (0.05<p<0.10). In this study, no difference was demonstrated in the apparent clearance rate (Cl_app), apparent first-order absorption rate constant (k_a), maximum serum drug concentration (C_max), time of maximum drug concentration (T_max) or absorption lag time (t_lag) for theophylline before and after treatment with erythromycin. With no apparent alteration in theophylline clearance following erythromycin coadministration, the decrease in the first-order elimination rate constant suggested that the apparent volume of distribution of theophylline is increased in the presence of erythromycin. It is concluded that patients maintained on theophylline derivatives should be closely monitored when erythromycin is coadministered.     

Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days

One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity inin vitro and inin vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study. Doses ranged from 50 to 1060 mg/m²d×3 days. Due to the possibility of local hemolysis with concentrations > 1.5 mg/ml, drug was administered in solutions containing 1.5 mg/ml. Because large volumes were needed at the higher dose levels, the infusion duration was increased from 2 hours to 4 hours. Mild to moderate nausea, vomiting, fatigue, dizziness and headaches were observed. Myelosuppression was the dose limiting toxicity. The recommended phase II dose and schedule was determined to be 800 mg/m²d×3d every 3 weeks. 773U82-HCl plasma concentration-time data were analyzed using a two-compartment pharmacokinetic model. The t1/2 averaged 6 hours and the total body clearance was 75.9 L/hr/m². The volume of distribution (Vdss) was large, averaging 470 L/m².Abbreviations ECG electrocardiogram - t^1/2 half-life - Vdss volume of distribution - HPLC highperformance liquid chromatography - Vd_ss steady-state volume of distribution - AUC area under the concentration × time curve - CL total body clearance - C_max peak plasma level - V_c central volume of distribution     

Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%^®-like fat emulsion (Diprivan-10^®, D) or as a 1%- or 6% emulsion in Lipofundin^® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (V_d,ss) and terminal half-life (t_{1/2, 2}) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both V_d,ss and t_{1/2, 2} (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,_{1/2, keo}) was observed compared to the other propofol formulations (p<0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.     

Gastric acid secretion in the dog: a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole

A mechanism-based pharmacodynamic model was used to describe the inhibitory effect by omeprazole on gastric acid secretion measured after histamine stimulation in the dog. The model identifies parameters that are related to the physiological system, the histamine stimulation, and the irreversible effect of omeprazole on the H⁺, K⁺-ATPase enzyme. Four different experiments with omeprazole (Exps. 1–4) and two placebo experiments were performed in each of the four Heidenhain pouch dogs used. For placebo and experiments 1–3, saline or omeprazole 0.81 mol/kg was infused during 3 hr with measurements of histamine-stimulated gastric acid secretion in two periods of 3.5–6.5 hr, one period starting just before the omeprazole infusion and a second later period up to 29 hr post infusion. In experiment 4, 0.18 mol/kg of omeprazole was infused for 22.5 min and gastric juice was collected for 5 hr post infusion. The response data was well described by the model. Similar parameter estimates were obtained by three different analysis methods; naïve pooling, two-stage method and nonlinear mixed effects modeling. The elimination rate constant for the H⁺, K⁺-ATPase enzyme, k _out, was estimated to be 0.040 hr^-1, corresponding to a half-life of about 17 hr. This rate constant determines the duration of omeprazole inhibition after long-term exposure. For short-term omeprazole exposure the duration is determined by the rate constant for transfer of enzymes from active to resting state, estimated to be 1.88 hr^-1. The second-order rate constant for histamine stimulation was estimated to be 0.064 hr^-1 per histamine concentration unit and the maximum acid secretion was estimated to be 5.0 mmol H⁺/30 min. The second-order rate constant for the irreversible binding of omeprazole to H⁺, K⁺-ATPase, k _ome, was estimated to be 2.39 L/mol hr. By modeling the histamine-induced baseline response simultaneously with active treatment, predictions of the response are possible not only following different dosing regimens of omeprazole, but also following different degrees of histamine stimulation.