Determinants of drug disposition in man

This article reviews some of the important determinants of variation in drug disposition such as age, gender, body weight, diet, environmental influences, drug - protein interactions, compliance, drug - drug interactions, endogenous substances, disease states, circadian variation and genetics.     

Rapid development of enhanced clearance after high-dose cyclophosphamide

We have studied the disposition of cyclophosphamide, its major cytotoxic metabolite phosphoramide mustard, and the synthetic glucocorticoid dexamethasone in nine patients receiving high-dose cyclophosphamide daily for 2 days before bone marrow transplantation. The total body clearance of cyclophosphamide was observed to increase from 93 +/- 27 ml/min on the first day to 178 +/- 83 ml/min on the second day. This was associated with an increase in the clearance of dexamethasone from 369 +/- 104 ml/min to 526 +/- 123 ml/min. An increased rate of formation of phosphoramide mustard with higher peak concentrations was also seen. Simulation studies show that these changes are most likely the result of an increase in the hepatic metabolism of cyclophosphamide. These results show that high-dose cyclophosphamide causes an increase in its own clearance and that of dexamethasone through an apparent induction of hepatic-metabolizing enzymes detectable 24 hours after initial exposure to cyclophosphamide.     

Correlation of cyclosporine and metabolite binding to cyclophilin and a 50 kDa binding protein with in vitro immunosuppression: a preliminary report

Seven purified cyclosporine (CsA) metabolites were analyzed for binding to cyclophilin and to a 50 kDa protein purified from a JURKAT cell line. In addition, the potency of the seven metabolites, relative to CsA, was obtained using a primary mixed lymphocyte culture (MLC) suppression assay. CsA, M1, 17, and 21 were found to be immunosuppressive in the concentration range used (0-500 ng/mL). These results were then compared to protein binding. CsA and metabolite 17 (M17) bound to both proteins. Conversely, M1, 13, 21, and 26 bound only to cyclophilin, while M8 and M18 bound only to the 50 kDa protein.     

Impact of Body Mass Index on Left Ventricular Function

Background

Obesity is associated with increased cardiovascular morbidity and mortality. A direct effect of isolated obesity on cardiac function is not well established. The study was designed to determine the direct effect of various grades of isolated obesity on echocardiographic indices of systolic and diastolic left ventricular function.

Methods

Fifty one obese and 25 normal weight, serving personnel without any other pathological condition were studied. Group I (n=25) consisted of subjects with normal weight and body mass index (BMI <25kg/m²), Group II (n=34) of overweight subjects (BMI 25-29.9 kg/m²) and Group III (n=17) of obese subjects (BMI >30 kg/m²). Echocardiographic indices of systolic and diastolic function were obtained and dysfunction was assumed when at least two values differed by ≥ 2 SD from the normal weight group.

Result

Ejection fraction, fractional shortening were increased (p<0.05) in Group II and III. Left ventricular dimensions were increased (p< 0.001) but relative wall thickness was unchanged. Systolic dysfunction was not observed in any of the obese patients. The mitral valve pressure half time (p< 0.01), left atrial diameter (p < 0.01) and the deceleration time were increased (p< 0.01) in obese subjects, while other diastolic variables were unchanged. No difference were found between obesity subgroups. Subclinical diastolic dysfunction was more prevalent among obese subjects. BMI correlated significantly with indices of left ventricular systolic and diastolic function.

Conclusion

Subclinical left ventricular diastolic dysfunction was noted in all grades of obesity which correlates with BMI.Key Words: Obesity, Systolic function, Diastolic function, Echocardiography     

An improved application for the enzyme multipled immunoassay technique for caffeine, amikacin, and methotrexate assays on the Dade-Behring Dimension RxL Max clinical chemistry system

Caffeine is widely used in children's hospitals to treat neonatal apnea. Amikacin is used for treating hospital-acquired infections caused by Gram-negative bacteria resistant to other aminoglycosides. The blood levels, however, have to be monitored carefully because of its ototoxicity and nephrotoxicity. Methotrexate (MTX) is used as a chemotherapeutic agent in the treatment of leukemia and lymphoma as well as of certain solid tumors. Current enzyme multiplied immunoassay technique (EMIT) assays for caffeine, amikacin, and MTX lack low-end precision. In addition, the EMIT assays for MTX lack the sensitivity of reliable quantification to 0.05 micromol/L needed because of today's more rigorous requirements. The goal of the present study was to optimize the EMIT method parameters on the Dimension RxL Max, thereby providing applications with improved precision for all the three analytes and enhancing the sensitivity of the EMIT methotrexate assay. Serum samples were measured for caffeine, amikacin, and MTX by EMIT on the Dimension RxL Max and by EMIT (on the Olympus AU 600 for caffeine) and fluorescence polarization immunoassay [for MTX and amikacin (FPIA; TDx FLx)] at Quest Diagnostics. The new instrument method parameters that use larger sample volumes and longer observation of optical density changes (caffeine, MTX) provide improved sensitivity for MTX permitting reliable measurement at 0.05 micromol/L and improved precision for all three analytes. Within- and between-day imprecision were less than 6% for low to high concentrations of caffeine and amikacin controls and are less than 7.5% for MTX concentrations greater than 0.3 micromol/L and 12.3% at 0.06 micromol/L. The correlation coefficients for caffeine, amikacin, and MTX plotted for the Dimension RxL Max versus the methods used at Quest Diagnostics were 0.973, 0.986, and 0.992, respectively. These EMIT method applications now compare well with other established assays. The new Dimension RxL Max method parameters provide greatly improved precision and also meet today's clinical sensitivity guidelines (0.05 micromol/L) for MTX.     

Ranitidine kinetics and dynamics. II. Intravenous dose studies and comparison with cimetidine

Intravenous ranitidine has been shown to reduce pentagastrin-stimulated gastric secretion. Eight normal men received, in randomized order, 60 mg ranitidine or 300 mg cimetidine intravenously over 2 min. Both ranitidine and cimetidine induced decreases in volume hydrogen ion content and pepsin activity of stimulated gastric juice. Ranitidine half-life (t1/2) was 2.1 +/- 0.1 hr and cimetidine (t1/2) was 1.5 +/- 0.1 hr. Ranitidine volume of distribution was 1.6 +/- 0.1 l/kg and that of cimetidine was 1.12 +/- 0.12 l/kg. The clearance of ranitidine was 0.54 +/- 0.04 l/kg hr-1 and that of cimetidine was 0.5 +/- 0.05 l/kg hr-1. It is suggested that the intravenous loading dose of ranitidine necessary to attain a serum concentration of 200 micrograms/l (which would achieve a 50% inhibition of gastric acid) is 0.3 mg/kg, followed by an infusion rate of 0.11 mg/kg hr-1.     

Thrombopoietin, but not erythropoietin, directly stimulates multilineage growth of primitive murine bone marrow progenitor cells in synergy with early acting cytokines: distinct interactions with the ligands for c-kit and FLT3

Thrombopoietin (Tpo), the ligand for c-mpl, has been shown to be the principal regulator of megakaryocytopoiesis and platelet production. The ability of Tpo to potently stimulate the growth of committed megakaryocyte (Mk) progenitor cells has been studied in detail. Murine fetal liver cells, highly enriched in primitive progenitors, have been shown to express c-mpl, but little is known about the ability of Tpo to stimulate the growth and differentiation of primitive multipotent bone marrow (BM) progenitor cells. Here, we show that Tpo alone and in combination with early acting cytokines can stimulate the growth and multilineage differentiation of Lin- Sca-1+ BM progenitor cells. In particular, Tpo potently synergized with the ligands for c-kit (stem cell factor [SCF]) and flt3 (FL) to stimulate an increase in the number and size of clones formed from Lin- Sca-1+ progenitors. When cells were plated at 1 cell per well, the synergistic effect of Tpo was observed both in fetal calf serum-supplemented and serum-depleted medium and was decreased if the addition of Tpo to cultures was delayed for as little as 24 hours, suggesting that Tpo is acting directly on the primitive progenitors. Tpo added to SCF + erythropoietin (Epo)-supplemented methylcellulose cultures potently enhanced the formation of multilineage colonies containing granulocytes, macrophages, erythrocytes, and Mks. SCF potently enhanced Tpo-stimulated production of high-ploidy Mks from Lin- Sca-1+ progenitors, whereas the increased growth response obtained when combining Tpo with FL did not translate into increased Mk production. The ability of Tpo and SCF to synergistically enhance the growth of Lin- Sca-1+ progenitors was predominantly observed in the more primitive rhodamine 123(lo) fraction. Tpo also enhanced growth of Lin- Sca-1+ progenitors when combined with interleukin-3 (IL-3) and IL-11 but not with IL-12, granulocyte colony-stimulating factor, granulocyte-macrophage colony- stimulating factor, or Epo. Epo, which has high homology to Tpo, was unable to stimulate the growth of Lin- Sca-1+ progenitors alone or in combination with SCF or FL, suggesting that c-mpl is expressed on more primitive stages of progenitors than the Epo receptor. Thus, the present studies show the potent ability of Tpo to enhance the growth of primitive multipotent murine BM progenitors in combination with multiple early acting cytokines and documents its unique ability to synergize with SCF to enhance Mk production from such progenitors.