Nimodipine: drug pharmacokinetics and plasma adenosine levels in patients affected by cerebral ischemia.
OBJECTIVE
Nimodipine is a dihydropyridine calcium channel blocker used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent investigations have shown that it is able to inhibit adenosine transport in human red blood cells and parietal cortex neurons. In this study we investigated the pharmacokinetics of nimodipine and the effect on plasma adenosine levels in patients affected by cerebral ischemia.


METHODS
Twelve patients with cerebral ischemia (9 men and 3 women; mean age, 68.8 +/- 11.2 years; mean weight, 67.9 +/- 9.3 kg) were admitted to the study. They received nimodipine intravenously (a bolus of 0.03 mg/kg) and orally (single doses of 30, 60, and 90 mg) during different sessions. Blood samples for adenosine and nimodipine were collected at fixed intervals up to 480 minutes. Adenosine and nimodipine plasma levels were detected by HPLC methods.


RESULTS
Both the intravenous and oral administrations induced a statistically significant increase in plasma adenosine levels (P <.001), which appeared to be related to the dose and route of drug administration. In particular, a 67.8% increase was observed after intravenous administration, and increases of 28.9%, 43.6%, and 60.2% were observed after 30 mg, 60 mg, and 90 mg of nimodipine, respectively. The pharmacokinetic parameters of nimodipine after intravenous administration were as follows: peak concentration (C(max)), 319.6 +/- 38.9 ng/mL at the first sampling time; area under the curve (AUC), 239 +/- 25 ng. h/mL; and terminal half-life, 3.12 +/- 0.97 hours. After oral administration, the drug kinetics was linear in the administered dose range and the pharmacokinetic parameters were as follows: C(max)(30 mg), 46.1 +/- 5.8 ng/mL; C(max)(60 mg), 81.7 +/- 14.6 ng/mL; C(max)(90 mg), 131.6 +/- 16.3 ng/mL; AUC(30 mg), 119 +/- 25 ng. h/mL; AUC(60 mg), 256 +/- 48 ng. h/mL; and AUC(90 mg), 389 +/- 54 ng. h/mL. The half-life was similar to the values observed after intravenous administration, whereas the bioavailability ranged between 2% and 5.9%.


CONCLUSIONS
Our data indicate that the administration of nimodipine induces an increase in plasma adenosine levels, and we hypothesize that the drug activity could be associated, at least partially, with adenosine mediation.
Blardi
Patrizia
P
Center of Clinical Pharmacology, Department of Internal Medicine, University of Siena, Italy. Blardi@unisi.it
Urso
Renato
R
De Lalla
Arianna
A
Volpi
Luciana
L
Perri
Tullio Di
TD
Auteri
Alberto
A
D000241:Adenosine / Q000097:blood*; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009553:Nimodipine / Q000493:pharmacokinetics*
D002121:Calcium Channel Blockers; D009553:Nimodipine; D000241:Adenosine