A SIMPLIFIED ACCOUNT OF DRUG ACCUMULATION AND STEADY-STATE DOSE EQUIVALENCES

The accumulation of medication taken regularly can influence its clini cal effects, cumulative toxicities and steady-state equivalent doses t o similar agents, and the elimination of concurrent medications. A bas ic expression of drug accumulation, the Unit Dose Accumulation Ratio ( UDAR), is defined as the ratio of the day-average blood drug concentra tion at steady-state to the peak blood drug concentration after one do se. In a single-compartment analysis the UDAR is found to equal 0.0601 multiplied by the elimination half-life fin hours). The UDARs estimat ed in this way approximate those found from measurements of valproic a cid, desipramine, and reboxetine. Further modeling reveals that in com mon situations graduality of release has only small effects on UDARs. Extension to multiexponential elimination is described by simple expre ssions in terms of ratios of kinetic coefficients. Modeling of accumul ation with biexponential elimination is depicted on a graph. Several a pplications of the UDAR are illustrated. The UDAR permits determinatio n of steady-state dose equivalences from single dose equivalences and vice-versa. This facilitates medication interchange, as in clinical wi thdrawal management by replacement of short-acting sedative-hypnotics with long-acting agents, e.g., alprazolam with clonazepam. The UDAR re flects tolerance, e.g., if 30-mg flurazepam equals 4-mg lorazepam, the UDAR indicates that at steady-state, 30 mg/day of flurazepam approxim ates 21 mg/day of lorazepam. The UDAR can estimate total exposure, e.g ., to organic chlorine. The UDAR complements methods described previou sly for drug dose prediction and blood drug level monitoring that were simplified by expressing blood levels as averages over the day.