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.

JACOB, MOIRE S. MD, FRCP(C); ZILM, DUANE H. PHD; MACLEOD, STUART M. MD, PHD, FRCP(C); SELLERS, EDWARD M. MD, PHD, FRCP(C) Author Information

From 3,548 drug overdose or abuse cases presenting at 21 Metropolitan Toronto hospitals' Emergency departments, data concerning demographic and medical characteristics, investigative and management procedures, drug analysis services, and disposition of patients were collected. Of the 3,548 cases, 2,723 (77%) were acute overdose and 816 (23%) were drug abuse. Drug overdose was more common than drug abuse for both sexes, but was more characteristic of females. The drugs most frequently alleged ingested were benzodiazepines (34%), ethanol (32%), salicylates (16%), and barbiturates (14%). The frequency with which particular classes of drugs are alleged in overdose corresponds closely to the frequency of prescribing these drugs in Ontario.

Persons admitted to hospital emergency rooms for treatment of drug misuse with concomitant alcohol use were generally found to be heavy drinkers.

Saliva samples were obtained from 25 hospital inpatients (14 males, 11 females, aged 19 to 79 years) taking diazepam (6 to 45 mg) daily. Despite interindividual variations in pharmacokinetics, a correlation was found between both dose and salivary diazepam concentration (r = 0.54, P less than 0.01) and dose and salivary N-desmethyldiazepam concentration (r = 0.78, P = 0.01). The correlation between the salivary concentration of diazepam and that of its metabolite is good (r = 0.76, P less than 0.01). The slope of this linear regression, 1.58, reflects the relative clearances of the metabolite and parent drug and agrees with the theoretical value, 1.60, obtained by calculation using known plasma pharmacokinetic and protein-binding parameters. There is a weak linear correlation of steady-state salivary benzodiazepine (drug and metabolite) concentration per milligram dose and age (r = 0.37, P less than 0.01).

The pattern of cardiac arrhythmias and their treatment, by propranolol and chlordiazepoxide, during the first 48 hr of alcohol withdrawal has been studied. Prior to treatment, the incidence of serious and life-threatening arrhythmias was found to be very low and uncorrelated with most biochemical parameters. Propranolol treatment, while efficacious in controlling arrhythmias, was limited due to its association with hallucinations. Chlordiazepoxide was associated with poor early control of arrhythmias. The combination of propranolol and chlordiazepoxide was found to perform best overall with substantial reductions in arrhythmias and the fewest treatment failures.