Daniel Salazar

Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass

Existing methods for predicting creatinine clearance provide accurate estimates for normal-weight patients but not for patients who are obese. Studies into this problem began with an animal model of obesity, the obese overfed rat. Mean creatinine clearance was found to vary in direct proportion to fat-free body mass, determined in both obese and normal animals. The relevance of this observation to renal function in humans was evaluated by analyzing published studies reporting creatinine clearance and creatinine excretion rates in obese and normal persons. Measured creatinine clearance correlated well with estimated fat-free body mass (r = 0.772, p less than 0.02), and urinary excretion of creatinine normalized to fat-free mass correlated impressively with age (r = 0.960). Formulas derived from these observations allow for the prediction of creatinine clearance at steady state: (formula; see text) In initial tests of these formulas, their predictions appeared to be as accurate as existing methods for the normal-weight population and far superior to these methods when applied to the obese population. Therefore, when creatinine clearance is not measured in obese patients, the estimation of this parameter with the proposed formulas should improve the ability to select the appropriate dose for drugs that are cleared principally by renal filtration.

Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics

A two-compartment closed model was used to characterize the movement of basophils between blood and extravascular sites resulting from methylprednisolone (MP) exposure. This model is consistent with the view that corticosteroids cause a decrease in the recirculation of these cells from peripheral compartments. Methylprednisolone (Solu-Medrol) was given to healthy males at doses of 10, 25, and 40 mg. Blood samples were collected and assayed for MP by HPLC for pharmacokinetic analysis. Whole blood histamine, an index of circulating basophils, was assessed by RIA over 32 hr. Nonlinear least-squares analysis was carried out to solve for the model parameters reflecting cell movement between compartments and sensitivity (IC50)to the steriod. This model quantitates the fall and return pattern of biologic response to corticosteroids with a minimal number of parameters which jointly fit several dose/response curves and yields a mean IC50value of 8.1 ng/ml similar to receptor binding of MP. Properties of the temporal and integrated response curve and model extrapolations over a wide dose range were explored with simulations. Because corticosteroids exert similar effects on other cells in blood, this model may be applicable to various regulatory and immunosuppressive effects.

Adriamycin-induced activation of NK activity may initially involve LAF production

SummaryC3HeB/FeJ spleen cells (unseparated or passaged over nylon wool columns) were cultured overnight (1∓2×106 cells/microwell) in the presence and absence of resident or ADM-induced PEC and anti-YAC-1 (4 h) NK activity was determined. The addition of resident PEC to spleen cells had little effect on NK activity. However, the addition of ADM-elicited PEC (10 mg/kg, IP, day −1 and day −5) to spleen cells prior to culture significantly augmented NK activity. If ADM-induced PEC were treated with carbonyl iron prior to coculture with spleen cells, augmentation of anti-YAC-1 activity was not observed. This suggested that ADM-activated macrophages augmented cultured splenic NK activity. Supernatants from overnight-cultured resident or ADM-induced adherent PEC were then prepared, dialyzed (to remove ADM), and tested for mitogenic activity or cocultured with spleen cells overnight. ADM-induced adherent PEC supernatants stimulated the proliferation of murine thymocytes (both LAF and IL-2 also stimulate) but not cultured CTL (only IL-2 stimulates). ADM-induced adherent PEC supernatants (as well as LAF, IL-2, and IFN) augmented overnight-cultured C3HeB/FeJ splenic NK activity. However, only IL-2 and IFN could augment overnight-cultured athymic BALB/c · nu/nu splenic NK activity. This suggested that ADM-elicited macrophages produce LAF which may act directly on NK cells or, more likely, may induce T cells to produce IL-2, IFN, or both.

Obesity as a risk factor in drug-induced organ injury. III. Increased liver and kidney injury by furosemide in the obese overfed rat.

Effects of the diuretic drug furosemide were examined in obese animals to evaluate the hypothesis that organ damage by reactive drug metabolites may be potentiated by this disease. Obese overfed Sprague-Dawley rats that were treated ip with 450 mg/kg furosemide on the basis of total body mass suffered a 58% mortality rate over 24 h. This contrasted with 0% mortality in animals of normal body mass. On the basis of median histopathology scores, organ necrosis was judged to be greater in the liver (2+) and kidneys (1+) of obese rats than in the liver (1+) and kidneys (less than 1+) of normal controls (p less than 0.05). Obese animals demonstrated a fourfold rise in fat mass over controls. The low solubility of furosemide in lipid makes it probable that aggravated drug toxicity in obese rats dosed to total body mass resulted in part from elevated furosemide concentrations in lean body mass. In a subsequent study designed to minimize this possibility, furosemide was administered on the basis of fat-free body mass to equalize initial drug exposure in obese and control rats. Even with this downward dosage adjustment, obese animals suffered increased hepatic necrosis (median score of 2+ versus 0 in treated controls), greater impairment of renal function (plasma creatinine concentration of 2.41 mg/dl versus 0.96 mg/dl in treated controls), and more extensive enzymuria (enzyme excretion 175-300% more elevated than in treated controls). In conclusion, obese rats appear to be at increased risk of furosemide-induced liver and kidney injury due to at least two factors: (1) increased exposure of target organs in lean body mass to furosemide when the dosing of this poorly lipophilic drug was based on total body mass, and (2) increased susceptibility of target organs in lean body mass to furosemide injury when dosing was adjusted downward to reflect fat-free body mass and to equalize initial drug exposure.

Augmentation of murine natural killer activity after culture

The augmentation of murine natural killer (NK) cell activity after culture is described. Increased NK cell activity occurred when spleen cells were cultured for 18 or 42 h at high cell density in macro culture plates at 37 degrees C. Similar results were also achieved using the same cell density when micro culture plates were employed. The simple modifications of culture conditions described in this paper should provide an excellent tool to study murine NK activity after culture. Furthermore, the micro culture system has the added advantage of enabling one to test large numbers of samples.