Anthony M. Yurchak

Effect of smoking on theophylline disposition

The pharmacokinetics of theophylline were examined in a group of nonsmokers and in heavy smokers (1 to 2 packs/day) before and 3 to 4 mo after cessation of cigarette smoking. The half‐life of theophylline in smokers averaged 4.3 (SD = 1.4) hr, significantly shorter than the mean value in nonsmokers (7.0, SD = 1.7 hr). The apparent volume of distribution of theophylline was somewhat larger in smokers (0.50 ± 0.12 L/kg) than in nonsmokers (0.38 ± 0.04 Llkg). The body clearance of theophylline was appreciably larger and relatively more variable in smokers (100 ± 44 ml/min/1.73 m2) than in nonsmokers (45 ± 13 ml/min/1.73 m2). Serum concentrations of thiocyanate, a biotransformation product of cyanide which is inhaled with smoke, were used to monitor the smoking status of the subjects. The body clearances of theophylline showed a good correlation (r = 0.785, p < 0.001) with the serum thiocyanate concentrations. Of the 8 smokers, only 4 managed to refrain from smoking for at least 3 mo, and these subjects showed no significant change in theophylline elimination. The increase in theophylline clearance caused by smoking is probably the result of induction of drug‐metabolizing enzymes that do not readily normalize after cessation of smoking.

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m2for the 5mg dose to 2271 ml/min/1.73 m2for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m2over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.

Enhanced biotransformation of theophylline in marihuana and tobacco smokers.

Single oral doses of theophylline were administered to 7 chronic marihuana smokers, to 7 chronic users of both marihuana and tobacco, and to 43 appropriate control subjects. Theophylline was cleared from the blood more rapidly in both marihuana and tobacco smokers with a mean increase in total clearance from 52 ml/kg/hr in nonsmokers to 74 ml/kg/hr in subjects who smoked either material alone. There was an additive increase in clearance to 93 m/lkg/hr in those who smoked both substances. Concern over enhanced metabolism of other drugs is probably warranted in tobacco and cannabis smokers.

Theophylline disposition in obesity

Theophylline disposition was examined in 14 obese subjects and 57 normal subjects. A single oral dose of aminophylline solution was given and serum and saliva samples were collected over several hours and assayed by high‐pressure liquid chromatography. The apparent volume of distribution (Vd) and body clearance (ClB) were analyzed for total body weight (TBW) and ideal body weight (IBW). The Vd averaged 0.482 (SD = 0.084) L/kg TBW in normals vs 0.382 (0.069) L/kg TBW and 0.77 (0.189) L/kg IBW in obese subjects. The ClB averaged 63.0 (28.5) ml/hr/kg IBW in normals compared to 32.8 (11.1) ml/hr/kg TBW and 64.1 (20.8) ml/hr/kg IBW in obese subjects. Similar Vd values between the two groups when TBW is used indicates that loading dose is best calculated based on TBW. Similar ClB based on lBW in normal and obese subjects indicates that lBW should be used to calculate maintenance doses for theophylline. Mean half‐lives were longer in obese subjects than in normals, 8.6 (2.0) and 6.0 (2.1) hr, respectively, suggesting that obese patients may need less frequent dosing.

Immunologic studies on aspirin: Clinical studies with aspiryl-protein conjugates

Abstract Aspiryl-chloride was conjugated with human serum albumin, human gamma globulin, rabbit gamma globulin, and poly- l -lysine. These conjugates were evaluated in skin tests, indirect hemagglutination, lymphocyte culture, and in an immunofluorescent test on tissues and sera of patients sensitive to aspirin. No evidence of specific immunologic reactions was found. Possible explanations for these results are discussed, and three possible nonimmunologic mechanisms for adverse reactions to aspirin are offered.

Effect of smoking on prednisone, prednisolone, and dexamethasone pharmacokinetics

The pharmacokinetics of oral prednisone and oral dexamethasone were examined in 18 healthy male adults. Eight subjects also received intravenous prednisolone and intravenous dexamethasone. Half of each group were cigarette smokers as confirmed by plasma thiocyanate concentrations. Plasma and urine concentrations of prednisone and prednisolone were assayed by high performance liquid chromatography, while plasma dexamethasone was measured by radioimmunoassay. There were no statistically significant differences between smokers and nonsmokers in the systemic availability of prednisolone (75 versus 84%), oral dose clearance of prednisone (29 versus 27 ml/min/kg), systemic prednisolone clearance (2.8 versus 2.9 ml/min/kg), or in the interconversion rates, volumes of distribution, or urinary recoveries of prednisone and prednisolone. Similarly, the pharmacokinetics of dexamethasone were unaffected by smoking. A limited correlation (r=0.55) was found between the high oral dose clearances of prednisone and the lower values of dexamethasone (6.73 and 5.71 ml/min/kg in smokers and nonsmokers). A two- to threefold variability occurred in oral dose clearances of each steroid with partial intrasubject covariance. Unlike the anticonvulsants, which markedly induce corticosteroid metabolism, smoking has no effect on their pharmacokinetics and should not complicate therapy with these drugs.

Prednisolone disposition in steroid-dependent asthmatics

A 40-mg intravenous dose of prednisolone was given as prednisolone phosphate to seven severe steroid-dependent asthmatics and to 13 healthy volunteers to determine if the large prednisone requirements of these patients were a function of the disease, cellular response, or rapid clearance of prednisolone. Plasma concentrations of prednisolone, prednisone, and cortisol were determined by high-performance liquid chromatography over an 8-hr test period. Circulating eosinophil concentrations were monitored concurrently. The apparent half-lifes of prednisolone in the asthmatics and normals were 3.33 +/- 0.71 and 3.25 +/- 0.58 hr (mean +/- SD). The apparent plasma clearances of prednisolone were 201 +/- 54 and 198 +/- 38 ml/min/1.73 m2 and the apparent volumes of distribution were 50.8 +/- 11.7 and 53.5 +/- 13.5 L/1.73 m2 for the asthmatic and normal groups, respectively. When the concentration-dependent binding of prednisolone to plasma protein was examined, no differences in the apparent clearances of unbound drug were found between the two groups. The eosinopenic response to prednisolone was similar in the steroid-dependent asthmatics and healthy normal volunteers. These studies indicate that binding, distribution, and clearance of prednisolone are not responsible for the large prednisone requirement of some steroid-dependent asthmatics. Differences in steroid-receptor sensitivity or in severity or pathophysiology of the disease state more likely account for the need for large prednisone dosages in these patients.

Identification of human reagins isolated with immunosorbent as IgE

Abstract An immunosorbent prepared by attaching covalently the constituents of the aqueous extract of ragweed pollen to aminocellulose was used to remove reagins from a fraction of allergic serum enriched with respect to skin-sensitizing activity. The adsorbed antibodies were eluted with a solution of 2M NaI, pH 9.1, or of glycine-HCl, pH 2.5. The presence of ragweed-binding IgE antibodies in these eluates was revealed by radioimmunoelectrophoresis and radio-Ouchterlony analysis. Guinea pigs, which had been rendered tolerant to normal human cord serum proteins, were immunised with these eluates and produced anti-IgE antibodies, as demonstrated by radioimmunodiffusion and by reversed PCA in monkeys. These results confirm that human reagins elicited to the allergens of ragweed pollen belong to the IgE class of immunoglobulins.