Serum protein and lipid concentrations as well as the serum protein binding of propranolol, diazepam and phenytoin were measured in normal weight and obese volunteers. Concentrations of alpha 1‐acid glycoprotein (AAG) in the obese subjects were double that of the lean controls. Conversely, concentrations of high density lipoproteins (HDL) were decreased in the obese group. The serum binding of propranolol was increased in the obese subjects and correlated with serum AAG concentrations. Diazepam binding was slightly decreased in the obese as a result of lower serum albumin concentrations and elevated free fatty acids. The binding of phenytoin was comparable in all of the volunteers. These findings point out some of the complex pathophysiologic changes associated with obesity which may in turn influence drug disposition and hence drug therapy in the obese patient.

Although clinically relevant, drug-protein interactions in the morbidly obese population have not been studied thoroughly. The objective of this study was to evaluate serum chemistry profiles and the degree of serum protein binding of propranolol, diazepam and phenytoin in the serum of four female, morbidly obese (> 190% of ideal body weight) and eight control female subjects. Serum triglyceride concentrations were higher and high-density lipoproteins were lower in the obese subjects than in the control group. Serum albumin and total protein concentrations in the obese were not different from controls. Unexpectedly, a,-acid glycoprotein concentrations were doubled in the obese subjects (mean obese value 121 mg 100 ml vs 62.9 mg, 100 ml for the control subjects). Obese subjects had a mean fraction unbound (fu) for propranolol of 0.086, which was significantly different from the controls (f, = 0.123). The binding of diazepam was decreased slightly in the obese subjects. The binding of phenytoin was similar in both groups.The altered serum chemistry of obesity may play a significant role in the drug management of the obese patient by altering drug-protein interactions.

1 The phenotyping parameters for dextromethorphan and mephenytoin were assessed in 48 normal male volunteers following administration of each metabolic probe drug on separate occasions and together according to a randomized 3-way crossover design. 2 Neither the urinary S-/R-mephenytoin ratio nor the dextromethorphan metabolic ratio were altered significantly by coadministration of the probe drugs. 3 Five-hundred and nineteen subjects were screened for expression of mephenytoin 4-hydroxylase and dextromethorphan O-demethylase activity following the coadministration of mephenytoin and dextromethorphan. The activity was determined in each case by methods not requiring any quantitative measurements. 4 Nineteen (3.7%) of the subjects were identified as poor metabolizers (PMs) of mephenytoin and 35 subjects (6.7%) as PMs of dextromethorphan. 5 All PMs of dextromethorphan were confirmed by more rigorous evaluation of the metabolic ratio.

The influence of age on tobramycin half-life, volume of distribution, and clearance was examined in 77 patients with infections due to gram-negative bacteria. All patients had normal renal function and hematocrits, were within 20% of their ideal body weight, did not receive penicillin antibiotics concurrently, and had a fever. Twenty-five patients were between 20 and 39 years of age, 23 patients were 40 to 59 years old, and 29 patients were in the age group 60 to 79 years. The mean half-lives were 2.3, 2.2, and 2.4 h, respectively, for the three age groupings. The average clearance and volume of distribution terms were, respectively, 1.34 ml/min per kg and 0.25 liter/kg for the younger group, 1.44 ml/min per kg and 0.26 liter/kg for the middle age group, and 1.25 ml/min per kg and 0.25 liter/kg for the older group. There was no significant difference among the three groups for any of the parameters (P > 0.05, analysis of variance). Correlation coefficients determined from individual plots of the three pharmacokinetic parameters versus age revealed no correlation between any parameter and age. Forty-five percent of the patients required doses greater than the recommended maximum (5 mg/kg per day) to achieve desired steady-state concentrations. Since tobramycin pharmacokinetics do not change as age increases, doses do not need to be arbitrarily changed in older patients with normal renal function.