Pharmacokinetic-pharmacodynamic profile of systemic nitric oxide-synthase inhibition with L-NMMA in humans.
OBJECTIVE
It has been demonstrated that inhibition of endothelium derived nitric oxide with NG-monomethyl-L-arginine (L-NMMA) results in a different cardiac and peripheral vascular response. The purpose of this study was to investigate the pharmacokinetic-pharmacodynamic profile of L-NMMA and pharmacokinetic interactions with L-arginine in healthy subjects.


METHODS
Plasma pharmacokinetics were analysed from two different studies: In study 1, 3 mg kg-1 L-NMMA was administered i.v. over 5 min and systemic haemodynamics, cardiac output (CO), fundus pulsation amplitude (FPA), and NO-exhalation (exhNO) were measured at baseline and 15, 65, 95, 155, and 305 min after start of drug administration (n=7). In study 2, 17 mg kg-1 min-1 of the physiologic substrate for nitric oxide synthase, L-arginine, was coinfused i.v. over 30 min with a primed constant infusion of 50 microg kg-1 min-1 L-NMMA (n=8).


RESULTS
Bolus infusion of L-NMMA resulted in a maximum plasma concentration of 12. 9+/-3.4 microg ml-1 (mean+/-s.d.) with elimination half-life of 63. 5+/-14.5 min and clearance of 12.2+/-3.5 ml min-1 kg-1 and caused a small hypertensive response, decreased CO by 13%, FPA by 26%, exhNO by 46% and increased systemic vascular resistance by 16% (P<0.05 each) 15 min after start of drug administration. Although only limited data points were available in the L-NMMA plasma concentration range between 0 and 4 microg ml-1, drug effects over time were in good agreement with an Emax model (r2>0.98 each), which also suggested that concentrations producing half-maximum effects were higher for FPA than for CO and exhNO. The coinfusion with L-arginine caused a nearly two-fold increase in plasma L-NMMA levels, indicating a pharmacokinetic interaction.


CONCLUSIONS
In the absence of a systemic hypertensive response, L-NMMA significantly decreased CO, exhNO, and FPA. The concentration calculated to produce a half maximal effect was equivalent for exhNO and CO, but markedly higher for FPA. Furthermore, measurement of FPA is susceptible to changes in L-NMMA levels at small plasma concentrations.
Mayer
B X
BX
Department of Clinical Pharmacology, University of Vienna, Austria.
Mensik
C
C
Krishnaswami
S
S
Derendorf
H
H
Eichler
H G
HG
Schmetterer
L
L
Wolzt
M
M
D000328:Adult; D019540:Area Under Curve; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001944:Breath Tests; D002302:Cardiac Output / Q000187:drug effects; D002829:Choroid / Q000098:blood supply; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005654:Fundus Oculi; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III; D011673:Pulsatile Flow / Q000187:drug effects; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000097:blood / Q000493:pharmacokinetics*
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III