تسجيل الدخول

تسجيل

Chronic dosing

المؤلف:  Sue Jickells , Adam Negrusz (Editors)

المصدر:  Clarkes Analytical Forensic Toxicology

الجزء والصفحة:  22

2026-09-14

54

Chronic dosing

Drugs accumulate in plasma or tissues if more than one dose is administered and the interval between the doses is less than the time taken to eliminate the previous dose. Under these circumstances, a change in the shapes of the plasma concentration–time and the tissue concentration–time curves also occurs. In all cases, accumulation is controlled by the size of the dose, the dose interval and the terminal elimination phase for loss of drug from the body (k_el). The problems of drug accumulation are of particular interest to the toxicologist because the resultant high drug concentrations may lead to a progressive and insidious toxicity. The extent to which a drug accumulates in multiple dosing can be estimated. After each successive dose, the maximum, minimum and average plasma concentrations will be higher than those for the previous dose. This is so in the early stages, but since drug elimination is often a first-order rate process, the total amount of drug in the body increases until the amount eliminated during a dose interval equals the amount taken in (total injected dose or the net absorbed dose after oral dosing). This is called steady state. The clearance (Cl) can be related to dose rate (D/s) divided by steady state plasma concentration (C_ss).

A good example of the importance of this concept is the use of methadone to treat opioid dependency. Methadone has a long pharmacokinetic half-life of about 24 h. At once-a-day dosing, the plasma concentrations of methadone accumulate for at least 5 days. Therefore, the effects of methadone increase during the first 5 days of therapy. If the dose consumed is too high, or dose increases are made during these 5 days, potentially life-threatening respiratory depression can set in. Repeated dosing leading to possible accumulation should be taken into account when interpreting the results of a toxicological analysis.