MULTI-FORTE, a microcomputer program for modelling and simulation of pharmacokinetic data

MULTI-FORTE is an expanded version of the MULTI non-linear fitting programs written by Yamaoka et al. The functions of the three original programs (including Gauss-Newton and Simplex fitting algorithms) have been combined and translated into FORTRAN 77 on the Macintosh computer for both speed and convenience. Models can be described in integrated equation form or as a system of differential equations. Bayesian estimation is also available. Improved numerical integration routines have been added including methods suitable for systems of 'stiff' differential equations (Fehlberg's 4/5 Runge-Kutta method and Gear's DIFSUB subroutine). MULTI-FORTE is a user-friendly program taking data from keyboard or disk file to produce output on screen, printer, or disk file in tables or printer-type plots

Effect of caffeine on ceftriaxone disposition and plasma protein binding in the rat

Previous studies have shown that caffeine can affect drug kinetics by altering drug binding to plasma protein, drug absorption, or drug distribution. In this study, the effect of caffeine on the in vivo protein binding and the disposition of ceftriaxone (a highly protein-bound cephalosporin) were investigated in the rat. Ceftriaxone 100mg/kg and caffeine 20mg/kg were i.v. injected via the tail vein and ceftriaxone in plasma, plasma filtrate, urine, feces, and tissues (brain, heart, kidney, liver, gut, lung, and muscle) was assayed by HPLC with UV detection. The fraction of free ceftriaxone in plasma ranged from 5.6 to 32.8% of total ceftriaxone (3-347 μg/ml) without caffeine and showed no alteration by caffeine. The total amount of ceftriaxone excreted in urine and feces was increased significantly (

Physiological pharmacokinetic model for the distribution and elimination of tenoxicam

A physiologically based pharmacokinetic model for tenoxicam distribution and excretion in the rat was developed. The drug concentrations in plasma and all the tissues except testis were simulated using flow-limited equations, while testis concentrations were calculated using a membrane-limited passive diffusion equation. The elimination of tenoxicam was described in the model by renal and hepatic (metabolic and biliary) excretion with gastro-intestinal secretion and reabsorption. In order to validate the model, 15 tissue samples, plasma (for free and total concentration), urine and feces samples were collected and assayed by HPLC after i.v. injection of tenoxicam (4.5 mg/kg). Good agreements between simulation and experimental data over a 24-h period following drug administration were obtained for plasma and tissues. The terminal half-life of tenoxicam was 8.8 h in plasma and ranged in tissues from 6.1 h in intestine to 10.6 h in brain. The fraction of free tenoxicam in plasma ranged from 1.2 to 2.1% of the total tenoxicam concentration (5.7-21.9 μ/ml)

Disposition of cefotaxime and its metabolite, desacetylcefotaxime, in rat: Application of a pharmacokinetic-protein binding model

1. The pharmacokinetics and protein binding of cefotaxime and desacetylcefotaxime were studied in rat. 2. After i.v. dosing of cefotaxime (100mg/kg) the concentration-time profiles of cefotaxime and its metabolite desacetylcefotaxime followed biphasic decays, giving the kinetic parameters for cefotaxime: VT ss and AUC of 127ml/kg and 8.2mg/min per ml, respectively. The elimination half-life was 17 min with Cls of 13.1 ml/min per kg. The average association constant (K x 103M-1) and total protein binding site concentration (Pt x 10-3M) for cefotaxime were 3.87 and 0.68, respectively, with saturation of plasma protein binding occurring at about 30 μg/ml. The average free fraction of cefotaxime in plasma (Fp) was 0.48. 3. The metabolite desacetylcefotaxime had a plasma Cmax of 74.4μg/ml (35 min). The respective elimination half-life and AUC were 53 min and 7.2 mg/min per ml. The binding profile, unlike that of cefotaxime, was non-saturable with a K value of 13.90M-1. The Fp of desacetylcefotaxime was 0.89. 4. The concentration-time behaviour of total and free desacetylcefotaxime (i.v. bolus, 50mg/kg) declined biexponentially with respective VTss and AUC of 125ml/kg and 19.4 mg/min per ml (total drug), and 192 ml/kg and 13.9 mg/min per ml (free drug). The phase half-life of total and free drug was about 36 min, whereas CLs (ml/min per kg) were 2.7 (total) and 3.7 (free). The binding characteristics were in good agreement with those of the metabolite produced in vivo, with a K value of 8.58M-1. The Fp value of desacetylcefotaxime in plasma was 0.73

Disposition of ceftriaxone in rat: Application of a pharmacokinetic-protein binding model and comparison with cefotaxime

1. The pharmacokinetic profile and protein binding parameters of ceftriaxone were determined in rat, and compared with those of cefotaxime. 2. Plasma concentration-time curves of ceftriaxone and cefotaxime (single i.v. bolus; 100mg/kg each) were described by a two-compartment, protein-binding model. 3. The corrected VT ss(ml/kg) of ceftriaxone was lower than that of cefotaxime. The AUCs of both drugs were similar. The t1/2 of the two drugs differed significantly, being 29min for ceftriaxone and 17min for cefotaxime. 4. In vivo protein binding constants of both drugs were similar, but the concentrations of protein binding sites differed significantly. The average free fractions in plasma (Fp) of ceftriaxone and cefotaxime were 0.22 and 0.48 respectively. 5. Saturation of the binding site for cefotaxime was estimated to occur at about 30 μg/ml in plasma, whereas saturation for ceftriaxone was seen at lower concentrations

Disposition of sulfadimethoxine in swine: Inclusion of protein binding factors in a pharmacokinetic model

Sulfadimethoxine was administered intravenously and orally to five swine. More than 75% of the dose was excreted into urine as the acetyl metabolite with 4-6% excreted unchanged. Plasma and urine data were not consistent when a linear pharmacokinetic model was used to describe the data. Sulfadimethoxine has a high affinity for plasma protein, and the data were subsequently fitted to a nonlinear model, which included saturable protein binding. The choice of a nonlinear model was further supported by a minimum value for the Akaike information criteria. The protein binding constant obtained was 2.8× 10 Mand the total protein binding site concentration in plasma was 4.6×10m. Both values are comparable with in vitro data. This result suggests that the nonlinear model involving protein binding can be successfully applied to pharmacokinetic data. The apparent biological half-life of Sulfadimethoxine (free and bound) in plasma was 14 hr; however, the half-life of elimination of free drug was 1.25 hr. Following oral administration, all of the dose was absorbed with an apparent absorption half-life of 2.9 hr