Pharmacokinetic-Pharmacodynamic modeling of the analgesic effect of bupredermTM, in mice

Purpose: BupredermTM-Buprenorphine transdermal delivery system (BTDS) was developed for the treatment of post-operative and chronic pains. This study examined the relationship between the plasma concentration of buprenorphine and its analgesic effect (tail flick test) in order to assess the usefulness of pharmacokinetic-pharmacodynamic (PK-PD) modeling in describing this relationship. Methods: After patch application, plasma concentrations of bu- prenorphine in mice were measured for 72 hours with a validated LC/MS/MS system, and the analgesic effects were assessed by tail flick test for the period of 24 hours. A modified two- compartment open model was used to explain the PK properties of BTDS, and the PD model was characterized by slow receptor binding. Results: The peak buprenorphine level in plasma was achieved at 1-24 h and the effective therapeutic drug concentration was maintained for 72 hours. BupredermTM induced prolongation of tail-flick latency in a dose and time dependent manner. Maximum analgesic effect was attained at 3-6 h and was maintained for 24 h after patch application. Counter-clockwise hysteresis between the plasma concentration and the analgesic efficacy of BTDS was observed after BupredermTM application, indicating there was a delay between plasma concentrations and the effect observed. From the developed PK-PD model, Kd values (0.69-0.82 nM) that were derived from the pharmacodynamic parameters (Kon and Koff) are similar to the reported values (Kd = 0.76 ± 0.14 nM). Good agreement between the predicted and observed values was noted for the rate of change in analgesic effect data (R2 = 0.822, 0.852 and 0.774 for 0.24, 0.8 and 2.4 mg/patch, respectively). Conclusions: The established PK- PD model successfully described the relationship between plasma concentration of buprenorphine and its analgesic efficacy measured by the tail flick test. Our model might be useful in estimation and prediction of onset, magnitude and time course of concentration and pharmacological effects of BTDS and will be useful to simulate PK-PD profiles with clinical regimens.

P-glycoprotein mediated interactions between Chinese materia medica and pharmaceutical drugs

P-glycoprotein(P-gp)is an important transmembrane ATP-binding cassette(ABC)drug efflux transporter expressed in various human tissues such as the intestines,liver,kidneys,and bloodbrain barrier.It limits the intracellular concentration of xenobiotics by pumping them out of the cells,affecting drug pharmacokinetics and therapeutic effects.With its broad substrate specificity,it has the potential to remove a wide range of drugs from Chinese materia medica(CMM),including conventional medicines and active compounds.Increasing evidence has confirmed the superior therapeutic effectiveness of CMM in treating a wide range of diseases worldwide,as well as in conjunction with western drugs.As a result,herbal medicine-drug compounds have prompted widespread concern,with the majority of these interactions involving transporters such as P-gp.This review systematically summarizes the inhibition or induction of P-gp expression/function by active CMM compounds and the underlying regulatory mechanisms.It will aid in improving understanding of the synergistic or inhibiting effects associated with transporter P-gp as well as rational safety concerns for using CMM,particularly in combination with drugs.