URINE ACIDIFICATION AFFECTS THE ACTIVITY OF THE ORGANIC-BASE TRANSPORTER IN A NONSTEREOSELECTIVE MANNER

This investigation determined 1) the effect of urine acidification on renal clearance (Cl-renal), total systemic clearance (Cl-total) and no nrenal clearance (Cl-nonrenal) of pindolol, 2) whether urine acidifica tion affected the stereoselectivity of pindolol excretion and 3) the p harmacodynamic effects that may result from changes in the activity of the organic base transporter. The Cl-renal), Cl-total and Cl-nonrenal values of pindolol isomers were determined during pindolol administra tion (10 mg twice daily; control phase) and during pindolol administra tion (10 mg twice daily) with NH4Cl, a systemic and urinary acidifier, (1.5 g every 6 hr). Eight healthy males (22-33 yr) randomly received this therapy for 3 days on two occasions. On day 4, urine and plasma w ere collected over 24 hr. R-(+) pindolol Cl-renal values during contro l and NH4Cl were 203 +/- 82 and 480 +/- 248 ml/min, respectively (P = .03). S-(-) pindolol Cl-renal values during control and NH4Cl were 279 +/- 81 and 593 +/- 294 ml/min, respectively (P = .005). NH,CI increas ed R-(+) pindolol Cl-renal by 173% +/- 136% (P = .003) and S-(-) pindo lol Cl-renal by 127% +/- 105% (P = .03). Stereoselective renal excreti on of pindolol was unaffected by NH4Cl; the R(+)/S(-) pindolol Cl-rena l ratio was unchanged from control to NH4Cl (0.74 +/- 0.23 to 0.81 +/- 0.10, P = NS, respectively). NH4Cl, however, affected pindolol Cl-non renal in a stereoselective fashion; R-(+) pindolol Cl-nonrenal values increased (641 +/- 241 to 851 +/- 251 ml/min; P = .02), whereas S-(-) pindolol Cl-nonrenal values remained constant (354 +/- 116 vs. 370 +/- 213 ml/min). Changes in pindolol clearance values resulted in a signi ficant reduction in beta-blocking activity assessed by isoproterenol t esting. We conclude that increasing the urine proton gradient can incr ease the Cl-renal value of organic bases by 2-fold in a manner that is not stereoselective. NH4Cl, however, did increase the Cl-nonrenal val ue of pindolol in a stereoselective manner. These data, therefore, ind icate that the administration of a urine-acidifying agent can greatly enhance the elimination of organic bases and ultimately reduce the pha rmacologic activity of the organic base.