An ex vivo investigation into the transurothelial permeability and bladder wall distribution of the nonsteroidal anti-inflammatory ketorolac.
Transurothelial drug delivery continues to be an attractive treatment option for a range of urological conditions; however, dosing regimens remain largely empirical. Recently, intravesical delivery of the nonsteroidal anti-inflammatory ketorolac has been shown to significantly reduce ureteral stent-related pain. While this latest development provides an opportunity for advancing the management of stent-related pain, clinical translation will undoubtedly require an understanding of the rate and extent of delivery of ketorolac into the bladder wall. Using an ex vivo porcine model, we evaluate the urothelial permeability and bladder wall distribution of ketorolac. The subsequent application of a pharmacokinetic (PK) model enables prediction of concentrations achieved in vivo. Ketorolac was applied to the urothelium and a transurothelial permeability coefficient (Kp) calculated. Relative drug distribution into the bladder wall after 90 min was determined. Ketorolac was able to permeate the urothelium (Kp = 2.63 × 10(-6) cm s(-1)), and after 90 min average concentrations of 400, 141 and 21 μg g(-1) were achieved in the urothelium, lamina propria and detrusor respectively. An average concentration of 87 μg g(-1) was achieved across the whole bladder wall. PK simulations (STELLA) were then carried out, using ex vivo values for Kp and muscle/saline partition coefficient (providing an estimation of vascular clearance), to predict 90 min in vivo ketorolac tissue concentrations. When dilution of the drug solution with urine and vascular clearance were taken into account, a reduced ketorolac concentration of 37 μg g(-1) across the whole bladder wall was predicted. These studies reveal crucial information about the urothelium's permeability to agents such as ketorolac and the concentrations achievable in the bladder wall. It would appear that levels of ketorolac delivered to the bladder wall intravesically would be sufficient to provide an anti-inflammatory effect. The combination of such ex vivo data and PK modeling provides an insight into the likelihood of achieving clinically relevant concentrations of drug following intravesical administration.
School of Pharmacy and Pharmaceutical Sciences, Cardiff University , Redwood Building, King Edward VII Avenue, Cardiff, U.K. , CF10 3NB.
Nicholas A
NA
Williams
Jenna L
JL
Bowen
Ghaith
G
Al-Jayyoussi
Mark
M
Gumbleton
Chris J
CJ
Allender
Jamie
J
Li
Tim
T
Harrah
Aditya
A
Raja
Hrishi B
HB
Joshi
D000283:Administration, Intravesical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003198:Computer Simulation; D016503:Drug Delivery Systems; D020910:Ketorolac / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007700:Kinetics; D013552:Swine; D014018:Tissue Distribution; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020910:Ketorolac
intravesical; ketorolac; pharmacokinetics; stent; urothelium