Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model.

The aim of this study was to predict the disposition of midazolam in individual surgical patients by physiologically based pharmacokinetic (PBPK) modeling and explore the causes of interindividual variability. Tissue-plasma partition coefficients (k(p)) were scaled from rat to human values by a physiologically realistic four-compartment model for each tissue, incorporating the measured unbound fraction (f(u)) of midazolam in the plasma of each patient. Body composition (lean body mass versus adipose tissue) was then estimated in each patient, and the volume of distribution at steady state (V(dss)) of midazolam was calculated. Total clearance (CL) was calculated from unbound intrinsic CL, f(u), and estimated hepatic blood flow. Curves of midazolam plasma concentration versus time were finally predicted by means of a perfusion-limited PBPK model and compared with measured data. In a first study on 14 young patients undergoing surgery with modest blood loss, V(dss) was predicted with an only 3.4% mean error (range -24-+39%) and a correlation between predicted and measured values of 0.818 (p < 0.001). Scaling of k(p) values by the four-compartment model gave better predictions of V(dss) than scaling using unbound k(p). In the PBPK modeling, the mean +/- standard deviation (SD) prediction error for all data was 9.7 +/- 33%. In a second study with 10 elderly patients undergoing orthopedic surgery, hemodilution and blood loss led to a higher f(u) of midazolam. The PBPK modeling correctly predicted a marked increase in V(dss), a smaller increase in CL, and a prolonged terminal half-life of midazolam, as compared with findings in the first study. Interindividual variation in the disposition of midazolam could thus in part be related to the physiological characteristics of the patients and the f(u) of the drug in their plasma.

Distribution and elimination of intravenously injected urinary trypsin inhibitor.

Elimination of human urinary trypsin inhibitor (UTI) after intravenous injection of 125I-labelled UTI was followed by serial plasma and urine samples in three male volunteers. The plasma half-life of 125IUTI during 0-3 h after injection was 33 min and during the following 4 hours the half-life was 2 hours. Free, biologically active inhibitor was found in the urine during the first four hours after injection. Most of the radioactivity in the urine, however, corresponded to free 125I probably released during the degradation of UTI in the kidney. The distribution of UTI was studied after injection of 125IUTI in rats by measurement of radioactivity in excised organs. Fifteen min after the injection 44% of the radioactivity was found in the kidneys and 9% in the liver, implying that the kidneys are the primary site of UTI metabolism.

Radioimmunological quantitation of the urinary trypsin inhibitor in normal blood and urine.

A radioimmunoassay for measurement of the urinary trypsin inhibitor in human serum and urine is described. Because of the immunological cross-reactivity between the inter-alpha-trypsin inhibitor and the urinary trypsin inhibitor the plasma and serum were treated with perchloric acid to precipitate the inter-alpha-trypsin inhibitor. Gel filtration of serum before and after acid treatment showed identical peaks corresponding to the urinary trypsin inhibitor. The normal level of the urinary trypsin inhibitor in fresh plasma from 30 blood donors was 6.38 +/- 0.33 mg/l (SEM), and in sera from 24 healthy volunteers 7.14 +/- 0.27 mg/l (SEM). In urine from 23 healthy volunteers the normal excretion was 8.17 +/- 1.18 mg/24 h (SEM).