Pharmacokinetics of cephacetrile in patients undergoing haemodialysis

Summary The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were:=5.03 h^–1,=0.458 h^–1, K₁₂=2.337 h^–1, K₂₁=1.996 h^–1 K₁₃=1.154 h^–1, V_c=5.508 l, V_p=6.448 l, Vd_ss=11.956 l.As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.     

Pharmacokinetic analysis of sparse in vivo NMR spectroscopy data using relative parameters and the population approach

NMR spectroscopy in vivo when applied to studying drugs and their metabolites usually measures relative concentration in a tissue over time. Only ratios of clearance and volume parameters can be estimated from these data. Low drug dosages (relative to the sensitivity of in vivo NMR) or rapid drug elimination create the additional problem of data sparsity where a pharmacokinetic model cannot be fitted individually. We have investigated whether relative and absolute pharmacokinetic parameters can be estimated from such data by applying a population model.The data analysed were relative concentractions of 5-fluorouracil (FU) and of the sum of its catabolits -fluoro--ureido-propanoic acid (FUPA) and -fluoro--alanine (FBAL) in te liver, as monitored in 16 cancer patients by [¹⁹F]-NMP spectroscopy during and after a 10-min intravenous infusion of 650 mg FU·m^–2. The structural part of the population model was a non-linear, two-compartment model featuring one FU compartment with volume V _FU , a saturable clearance of FU by conversion into the catabolites where CL=v _max /(k _M +C _FU ), a catabolite compartment with volume V _cat , and a concentration-independent clearance of the catabolites, CL _cat . The parameters actually fitted were: , v _max , k _M ·V _FU , V _cat /V _FU , and CL _cat /V _cat where is a proportionality factor relating the NMR signal intensity of FU to the amount of FU in the body and, therefore, has no purely pharmacokinetic interpretation. All parameters were checked for random interindividual variation; and v _max were also tested for inter-occasion variation. The program system NONMEM was used for model fitting.The estimated mean population parameters were: v _max =121 mol·min^–1, k _M ·V _FU =2590 mol, V _cat /V _FU =0.0648, CL _cat /V _cat =0.0555·min^–1. The proportionality factor was found to depend on body weight and, in addition, to have an inter-occasion random variation (within patients, between examinations). No other random variation of a kinetic parameter could be identified. The estimated v _max is similar to a reported estimate of 2.02 mol·min^–1·kg^–1 derived from FU plasma kinetics.This study shows that sparse relative concentration data can be analysed by using relative parameters in a population model. Only one parameter has no unequivocal pharmacokinetic meaning due to the lack of absolute concentration information. Any contribution of the measuring procedure to the inter-occasion variation of in vivo NMP spectroscopy measurements should be minimized in order to allow the detection of possible inter-individual variances of the pharmacokinetic parameters.Dedicated to Prof. Dr. Rudolf Preussmann on the occasion of his 65th birthday     

Pharmacokinetics of cephacetrile in patients with normal or impaired renal function

Summary The pharmacokinetics of cephacetrile, administered as a single i. v. injection of 15 mg/kg, have been determined in 8 patients with normal renal function and in 12 patients with a varying degree of renal impairment. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of antibiotic in the central and peripheral compartments. In patients with normal renal function the following values were obtained for various pharmacokinetic parameters: =3.971 h^–1; =0.343 h^–1; K₁₂=1.745 h^–1; K₂₁=0.763 h^–1; K_el=1.793 h_–1; V_c=8.181; V_p=18.401 and V_dss=26.581. Cephacetrile had some of the highest apparent distribution volumes of all the cephalosporins. Impaired renal function significantly affected , , K₁₂, and K_el. A linear relationship between K_el of cephacetrile and creatinine clearance was demonstrated. The elimination of cephacetrile in anuric patients was about ten times slower than in patients with normal renal function.     

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.     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

Formation of cyanide after i. v. administration of the oxime HI 6 to dogs

HI6(pyridinium, 1-[[[4-(aminocarbonyl)pyridinio] methoxy]methyl]-2-[(hydroxyimino)methyl]-dichloride belongs to a series of bisquaternary pyridinium oximes that are effective against poisoning with extremely toxic organophosphates. Since HI6 has been shown to be unstable at pH 7.4 and to release significant amounts of cyanide, a study was undertaken to determine the degree of cyanide formation from HI 6 in vivo. When HI 6 (100 mol/kg) was administered i. v. to dogs, the animals showed no signs of cyanide toxicity but exhibited some cholinomimetic symptoms, including retching, hypersalivation and enhanced intestinal motility. Cyanide content in whole blood was monitored after production of methemoglobinemia (30%) by 4-dimethylaminophenol in order to sequester cyanide within red cells. Maximal cyanide contents of 20 mol/l were found in blood after 90 min. Calculation of the area under the concentration versus time curve for blood cyanide indicates that about 4% of HI 6 produced cyanide. Determination of the pharmacokinetic parameters of HI 6 (V_D=0.31 l/kg; k_el=0.76 h^–1) and of cyanide (V_D=0.086 l/kg; k_el=0.52 h^–1) together with the apparent first order rate constant of cyanide formation from HI 6 in vitro (0.174 h^–1, pH 7.4, 37°) allowed the simulation of a cyanide concentration curve that fitted with the experimental data points, indicating that cyanide formation in vivo was not bio-catalyzed. It is concluded that cyanide formation from HI 6 may not be regarded as a potential hazard, since cyanide elimination exceeded markedly its formation. Whether this conclusion also holds true for man has to be established.     

Pharmacokinetics of tiaprofenic acid in children after a single oral dose

Summary. Twelve healthy children in three age groups anaesthetized for minor surgery were given a single oral dose of tiaprofenic acid (3 mg · kg^–1) (TA). Seven blood samples and zero to 8 and 8 to 24 h urines were collected. TA concentrations in plasma and urine were measured by HPLC.No significant difference was found between the age groups in the kinetic parameters of TA and no correlation was found between these parameters and age; t_max=2.12h, C_max=8.78mg · l^–1, AUC_{(08 h)} 33.9mg · h · l^–1, AUC=39.3 mg · h · l^–1, t_1/2=2.35 h, V_z=0.319 l · kg^–1, CL=0.094 l · h^–1 · kg^–1. Renal clearance was 14 ml · h^–1. kg^–1. 33% of the TA dose was recovered in the 24 h urine, 48% of which was conjugated, whereas in adults, TA is only found in urine as conjugates.The apparent plasma clearance was significantly higher (56%) than in 12 healthy adults given 1.5 mg · kg^–1 TA. Volume of distribution and t_1/2 did not significantly differ between children and adults. Since no relationship has been established between plasma TA and either efficacy or toxicity, a different dose regimen cannot be recommended in 3–11 year-old children from that in adults.     

Pharmacokinetics of sulfaethidole in the rat: Nonlinear multicompartment solution

Sulfaethidole distribution and elimination in the rat was studied over a 90-fold dose range. This experimental design produced marked nonlinearity in the binding of Sulfaethidole to proteins in both interstitial fluid and plasma. Using a multicompartmental model consisting of binding of Sulfaethidole to plasma and interstitial fluid proteins, Sulfaethidole distribution in the body could be simulated. Urinary and biliary elimination of Sulfaethidole depended on the unbound drug mass in the plasma and urine flow. The results confirm the central role of the unbound species in the distribution and elimination of drugs with marked binding to plasma proteins.Nomenclature A ₁ amount of drug in plasma (mg) - A ₂ amount of drug in interstitial fluid (mg) - A ₃ amount of drug in poorly perfused tissues (mg) - A ₄ amount of drug in highly perfused tissues (mg) - fu ₁ fraction of total drug in plasma unbound (dimensionless) - fu ₂ fraction of total drug in interstitial fluid unbound (dimensionless) - fb ₁₁ fraction of drug bound to first binding site on plasma protein (dimensionless) - fb ₁₂ fraction of drug bound to second binding site on plasma protein (dimensionless) - fb ₂₁ fraction of drug bound to first binding site on interstitial fluid protein (dimensionless) - fb ₂₂ fraction of drug bound to second binding site on interstitial fluid protein (dimensionless) - K _d,1 apparent dissociation constant of first binding site on protein (dimensionless) - K _d,2 apparent dissociation constant of second binding site on protein (dimensionless) - B _max,11 ^–1 inverse of maximal binding capacity of first binding site on plasma protein (ml/mg) - B _max ^12–1 inverse of maximal binding capacity of second binding site on plasma protein (ml/mg) - B _max,21 ^–1 inverse of maximal binding capacity of first binding site on interstitial fluid protein (ml/mg) - B _max,22 ^–1 inverse of maximal binding capacity of second binding site on interstitial fluid protein (ml/mg) - k ₁₂ fractional transport rate of unbound drug from plasma to interstitial fluid (h^–1) - k ₂₁ fractional transport rate of unbound drug from interstitial fluid to plasma (h^–1) - k ₂₃ fractional transport rate of unbound drug from interstitial fluid to poorly perfused tissues (h^–1) - k ₃₂ fractional transport rate of unbound drug from poorly perfused tissues to interstitial fluid (h^–1) - k ₁₀ fractional rate of elimination of unbound drug from plasma (h^–1) - k ₁₀ ⁰ value during the first 210 min - k ₁₀ ¹ value after 270 min, linearly increased between 210 and 270 min (Eq. 5) - fup _t fraction of instantaneous binding of drug between plasma unbound drug and highly perfused tissue (dimensionless) - V _p plasma volume (ml) - V _is interstitial fluid volume (ml)     

Pharmacokinetics of quinidine related to plasma protein binding in man

Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant () varied from 0.071 to 0.146 h^–1 (mean 0.113), and apparent volume of distribution (V) varied from 1.39–3.20 l · kg^–1 (mean 2.27). Total body clearance was 2.32–6.49 ml min^–1 · kg^–1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both V (r=0.885, p<0.01) and total body clearance (r=0.668, p<0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.     

The pharmacokinetics of carbamazepine

Summary The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:k _abs =0.176±0.209 h^–1;k=0.0203±0.0055 h^–1; T_1/2=37.5±13.1 h; V_D=0.825±0.1041 · kg^–1; Clearance=0.0163±0.0061 l · kg^–1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.     

Stability of Lidocaine in Aqueous Solution: Effect of Temperature,pH, Buffer,and Metal Ions on Amide Hydrolysis

The degradation of lidocaine in aqueous solution obeys the expression k _obs = (k _H+[H ⁺] + k _o ) [H⁺]/([H ⁺ ] + K _a + k_o K _a([H ⁺ ] + K _a) where k _H+ is the rate constant for hydronium ion catalysis, and k _o and k_o are the rate constants for the spontaneous (or water-catalyzed) reactions of protonated and free-base lidocaine. At 80°C, the rate constants for these processes are 1.31 × 10^–7 M ^–l sec^–1, 1.37 × 10^–9 sec^–1, and 7.02 × 10^–9sec^–1; the corresponding activation energies are 30.5, 33.8, and 26.3 kcal mol^–1, respectively. It was found that the room temperature pH of maximum stability is 3–6 and that lidocaine is more reactive in the presence of metal ions such as Fe²⁺ and Cu²⁺. The dissociation constant, K _a, for lidocaine at 25–80°C was also measured at 0.1 M ionic strength and a plot of pK _a versus 1/T gave a slope of (1.88 ± 0.05) × 10³ K^–1 and intercept 1.56 ± 0.16.     

Albendazole kinetics in patients with echinococcosis: Delayed absorption and impaired elimination in cholestasis

Summary The pharmacokinetics of albendazole and its main metabolite, albendazole sulphoxide, have been examined after giving a single oral dose of 200 mg albendazole to 19 patients with either Echinococcus multilocularis or E. granulosus, 5 of whom had significant extrahepatic obstruction due to the underlying disease. The AUC of albendazole sulphoxide was increased in the latter patients (mean 122 mol · h · l^–1 compared to 17 mol · h · l^–1 in the non-obstructed group). Obstructed patients had delayed absorption, k_a averaging 0.39 compared to 1.41 h^–1 in non-obstructed patients. The corresponding elimination rate constant, k_e was also prolonged, averaging 0.041 and 0.13 h^–1 in the two groups, respectively. Four patients were restudied after complete or partial resolution of the cholestasis. The pharmacokinetic parameters in them had returned towards values comparable to those in the non-obstructed patients.     

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.     

Effect of renal insufficiency on the pharmacokinetics of cyclophosphamide and some of its metabolites

Summary Cyclophosphamide pharmacokinetics were studied in seven patients with moderate to severe renal insufficiency (creatinine clearances 0–51 ml · min^–1), and compared with a matched control group of patients with normal renal function. The mean half-life of cyclophosphamide following intravenous administration in the normal group was 8.21±2.33 (SD) h whilst that in renal failure was 10.15±1.80 h: these were significantly different. The total body clearance in the normal control group was 58.6±10.9 ml·kg^–1h^–1 which was significantly larger than in renal failure where it was 48.8±10.9 ml·kg^–1h^–1. V_d , V_{d ss} and V_c were not significantly different between the two groups. A linear relationship exists between , the first order disposition rate constant and endogenous creatinine clearance since this drug shows a relatively small degree of compartmentalisation. The plasma half-life of phosphoramide mustard, a cytotoxic metabolite of cyclophosphamide, shows a parallel and significant increase in renal failure with the parent compound. The t_1/2 in normal patients was 8.33±2.0 h, whilst in the renal failure group it was 13.37±4.23 h. Total alkylating activity as measured by the nitrobenzylpyridine reaction showed a significant increase in renal failure. This data suggests that in pharmacokinetic terms it may not be necessary to alter the dose of cyclophosphamide until there is severe renal impairment. Further studies correlating the efficacy and toxicity of the drug with its pharmacokinetics in renal failure are necessary.     

Application of a radioreceptor assay in a pharmacokinetic study of oxitropium bromide in healthy volunteers after single i.v., oral and inhalation doses

Summary Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the¹⁴C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and³H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg·ml^–1 and 3 ng·ml^–1 for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design.After i.v. administration the kinetic parameters were: V_c 38.4 l; t_1/2 5.3 min; t_1/2 142 min; AUC 8.9 h·ng·ml^–1; renal excretion 50.2%, k₁₀ 3.5 l·h^–1 and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug.     

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its ₁-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung ₁-and rat reticulocyte ₂-adrenoceptors.The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (C_max) of R,S-metoprolol after administration of the conventional formulation was 140 ng·ml^–1, (n=7) and it was approximately one-third of that after the sustained-release formulation, 49 ng·ml^–1, (n=6); the AUC_{0–24 h}-values for the formulations were 700 and 310 ng·h·ml^–1, respectively. The C_max for the ₁-adrenoceptor binding component of metoprolol was 180 ng·ml^–1 (n=7) after administration of the conventional, and 74 ng·ml^–1 after administration of the sustained-release formulation. The corresponding AUC_{0–24 h}-values for the receptor binding component were 920 and 470 ng·h·ml^–1 (n=7).Thus, the kinetic differences between R,S-metoprolol and the ₁-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage ₁- and ₂-adrenoceptor occupancy of metoprolol in plasma was 5–15% less than after administration of the conventional formulation. At 0.5–1.5 h after drug intake the average ₁-adrenoceptor occupancy of the conventional formulation varied between 80–90% and that of the sustained release formulation between 20–76%. At these times the differences in receptor occupancy were significant; at 0.5–2 h after drug intake the average ₂-adrenoceptor occupancy of the conventional formulation varied from 20–30%, and that of the sustained-release formulation was 2–17%. At other times the difference in receptor occupancy between the formulations was not significant.The results demonstrate that plasma concentration-kinetics were more discriminating than -adrenoceptor-binding in analysing bioequivalence. It was possible to determine the bioavailability of the active ingredient of metoprolol and to study pharmacodynamic bioequivalence by using receptor binding assays.     

Access of HTB, main metabolite of triflusal, to cerebrospinal fluid in healthy volunteers

Objective Triflusal has been shown to exert neuroprotective effects by downregulating molecules considered responsible for the development of Alzheimers disease (AD). The aim of this study was to develop a population pharmacokinetic model to characterize plasma and cerebrospinal fluid (CSF) pharmacokinetics of the main active metabolite of triflusal—HTB (2-hydroxy-4-trifluoro-methylbenzoic acid)—in healthy volunteers.Methods Data from two studies were combined. Study A: subjects received single oral doses of triflusal 900 mg. Triflusal and HTB plasma concentrations were extensively measured. Study B: triflusal 600 mg once daily was administered orally for 14 days. HTB plasma and CSF concentrations were determined in healthy volunteers. Population pharmacokinetic modeling was performed using NONMEM.Results A one-compartmental model with rapid first-order absorption for triflusal and first-order formation of HTB best described plasma concentrations. Triflusal elimination rate constant was 50 times faster than that estimated for the metabolite. CSF concentrations of HTB ranged between 0.011 g/ml and 0.341 g/ml. A CSF–plasma partition coefficient of 0.002 and a k_e0 value of 0.059 h^–1 were estimated by means of population modeling.Conclusion In the present study in healthy volunteers, HTB penetrated into the CSF in a range of concentrations experimentally proven to have protective effects in AD. These concentrations suggest that triflusal could be used in the treatment of central nervous system diseases in doses similar to those used in cardiovascular diseases. Access to the CSF compartment was characterized by a slow equilibrium rate constant and a low CSF–plasma partition coefficient.     

Pharmacokinetics of ketorolac tromethamine in humans after intravenous,intramuscular and oral administration

Summary The pharmacokinetics of ketorolac tromethamine, a potent non-narcotic analgesic agent used for relief of moderate to severe pain, has been studied in 15 healthy volunteers who received single 10 mg doses intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.) in a three-way cross-over design.The kinetics of i.v. ketorolac were characterized by a terminal half-life of 5.09 h, a small plasma clearance (CL = 0.35 ml·min^–1·kg^–1) and a small tissue distribution (V_ss=0.111·kg^–1, V=0.17 l·kg^–1; mean (SD). Following i.m. and p.o. administration, peak levels of approximately 0.8 µg/ml were rapidly attained (t_max = 0.8 and 0.9 h, respectively) and the systemic bioavailability was essentially complete.     

Application of a Combined “Effect Compartment/Indirect Response Model” to the Central Nervous System Effects of Tiagabine in the Rat

Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg ^–1 ml min ^-1 kg^–1, 1.50.1 L kg^–1 and 200.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were k_eo=0.030 min ^–1 and k_out=81 min^–1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates were E₀=155 6 V, E_max=100 5 V, EC₅₀=287 7 ng ml^–1, Hill factor=1.8 0.2 and k_eo=0.030 0.002 min ^–1. The results of this analysis show that for tiagabine the combined effect compartment-indirect response model can be simplified to the classical effect compartment model.     

Analysis of the pharmacokinetics of lithium in man

Summary An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant () of 0.035 h^–1±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory -phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (V_c) was 0.307 1 kg^–1±0.046 SD, less than half that of V_de at equilibrium. V_d (V_darea) was 0.8291 kg^–1±0.184 SD and mean total body clearance was 27.6 ml kg^–1 h^–1±4.7 SD.