Correspondence
Reduced Coronary Vasodilator Function after Myocardial Infarction
N Engl J Med 1994; 331:1590-1591December 8, 1994
- Article
To the Editor:
Uren et al. (July 28 issue)1 conclude that the coronary vasodilator response is severely impaired after myocardial infarction, in both infarcted and uninfarcted myocardial regions. However, the results of their studies are complicated by other important changes that occur during and after myocardial infarction, which were not considered.
Dipyridamole is a basic, lipophilic drug that is extensively and avidly bound to serum protein and has a relatively high rate of clearance.2 At relevant concentrations, over 99 percent of dipyridamole is bound to α1-acid glycoprotein.2 Myocardial infarction causes dramatic (over twofold) time-dependent increases in the concentrations of this and other acute-phase plasma proteins, which peak about one week after infarction and return to normal levels after three months.3 Such increases in protein concentrations can cause proportional reductions in the unbound-drug concentration in plasma, particularly if the drug is extensively protein-bound and has a high rate of systemic clearance.4
Since the unbound-drug concentration is typically considered responsible for eliciting pharmacologic action, a reduction in the response would be predicted. Such behavior has been shown for several other drugs with similar protein-binding characteristics.4,5 Therefore, an alternative explanation for the change in the response to dipyridamole is that concentrations of the free (pharmacologically available) drug were reduced one week after infarction because of increased binding to α1-acid glycoprotein in plasma.
5 ReferencesJohn Anthony Bauer, Ph.D.
State University of New York School of Pharmacy, Buffalo, NY 14260-12001
Uren NG ,Crake T ,Lefroy DC ,de Silva R ,Davies GJ ,Maseri A . Reduced coronary vasodilator function in infarcted and normal myocardium after myocardial infarction. N Engl J Med 1994;331:222-227
Full Text | Web of Science | Medline2
Mahony C ,Wolfram KM ,Cocchetto DM ,Bjornsson TD . Dipyridamol kinetics. Clin Pharmacol Ther 1982;31:330-338
CrossRef | Web of Science | Medline3
Agostoni A ,Vergani C ,Stabilini R , et al. Immunochemical quantitation of acute phase reactive proteins in myocardial infarction. Am Heart J 1970;80:313-318
CrossRef | Web of Science | Medline4
Piafsky KM . Disease-induced changes in the plasma binding of basic drugs. Clin Pharmacokinet 1980;5:246-262
CrossRef | Web of Science | Medline5
Routledge PA ,Stargell WW ,Wagner GS ,Shand DG . Increased plasma propranolol binding in myocardial infarction. Br J Clin Pharmacol 1980;9:438-440
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Bauer comments on the possible role of changes in the pharmacokinetics of dipyridamole as an explanation for our observations. In brief, we demonstrated that there was a reduced coronary vasodilator response to intravenous dipyridamole in myocardium remote from the site of infarction after eight days, with an improvement in the response six months after infarction. Dipyridamole is highly bound both to albumin and to α1-acid glycoprotein under steady-state conditions,1 and there is an increase of up to 100 percent in the latter protein because of an acute-phase reaction early after myocardial infarction.2
Dr. Bauer suggests that this increase may reduce the proportion of unbound drug in the plasma, which may account for the reduced pharmacologic action of dipyridamole after myocardial infarction.3 However, this is not borne out by previous studies. MacGregor and Sardi investigated the in vitro protein binding of dipyridamole in plasma and buffered protein solutions by equilibrium dialysis.4 They confirmed that albumin and α1-acid glycoprotein together were responsible for the high degree of protein binding of dipyridamole (95 to 99 percent protein-bound) and showed that the free-drug concentration remained constant over a range of 1 to 10 μg per milliliter, which is the range of concentrations normally reported in vivo after standard therapeutic oral or intravenous doses of dipyridamole.4 In addition, to simulate the increase in acute-phase proteins that occurs with myocardial infarction, the concentration of α1-acid glycoprotein was increased up to fivefold in human plasma in the same assay system, but with no effect whatsoever on the free fraction of dipyridamole.4 This result suggests that the concentration of unbound drug would not be affected by an increase of up to 100 percent in the α1-acid glycoprotein concentration after myocardial infarction.
Similarly, previous work has shown that the increase in the α1-acid glycoprotein concentration after myocardial infarction accounts for a cumulative increase in the total plasma lidocaine concentration when that drug is delivered by a constant intravenous infusion over 48 hours.5 Lidocaine is also largely protein-bound, with a much higher total plasma clearance rate than that of dipyridamole,1,5 yet the increase in the α1-acid glycoprotein concentration does not account for any change in the free-lidocaine concentration.5 For this reason, we do not believe that any change in acute-phase proteins explains the reduction in the coronary vasodilator reserve that we observed in the early period after myocardial infarction.
5 ReferencesNeal G. Uren, M.D.
David C. Lefroy, M.R.C.P.
Tom Crake, M.D.
Glenfield General Hospital, Leicester LE3 9QF, United Kingdom1
Mahony C ,Wolfram KM ,Cocchetto DM ,Bjornsson TD . Dipyridamol kinetics. Clin Pharmacol Ther 1982;31:330-338
CrossRef | Web of Science | Medline2
Agostoni A ,Vergani C ,Stabilini R , et al. Immunochemical quantitation of acute phase reactive proteins in myocardial infarction. Am Heart J 1970;80:313-318
CrossRef | Web of Science | Medline3
West JW ,Bellet S ,Manzoli UC ,Muller OF . Effects of Persantin (RA8), a new coronary vasodilator, on coronary blood flow and cardiac dynamics in the dog. Circ Res 1962;10:35-44
Web of Science | Medline4
MacGregor TR ,Sardi ED . In vitro protein binding behavior of dipyridamole. J Pharm Sci 1991;80:119-120
CrossRef | Web of Science | Medline5
Routledge PA ,Shand DG ,Barchowsky A ,Wagner G ,Stargel WW . Relationship between α1-acid glycoprotein and lidocaine disposition in myocardial infarction. Clin Pharmacol Ther 1981;30:154-157
CrossRef | Web of Science | Medline
