DOES HYDRALAZINE AFFECT β-BLOCKER PHARMACOKINETICS

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  • clinical pharmacology DOES HYDRALAZINE AFFECT ~-BLOCKER PHARMACOKINETICS

    Only with metoprolol or others with extensive first-pass metabolism Hydralazine and ~-blockers are often used in combination in antihypertensive therapy, but it is not known whether the increased splanchnic and renal blood flow resulting from hydralazine affects the kinetics of the ~-blockers. IS subjects took single oral doses of either metoprolol ( l OOmg; 15 subjects), nadolol (80mg; 7 subjects) or acebutolol (400mg; 7 subjects). Each subject was also randomly allocated to receive either hydralazine (50mg), l hour prior to the ~-blocker, or no additional drug, with at least one week between treatments. Mean metoprolollevels after combined treatment were raised, compared with the levels of metoprolol when given alone, resulting in the area under the curve (A UC) and maximum plasma concentration being significantly increased ( 1648 vs 1263ng/ ml hours; and 315 vs 211 ng/ ml respectively). The time to peak plasma level, and the renal clearance were both reduced after hydralazine, but not significantly. Elimination half-life, and the percentage of unchanged drug excreted were very similar in both treatments. The most likely reason for these results is that metoprolol undergoes considerable first-pass metabolism, which is affected by an increase in splachnic blood flow after hydralazine. The AUC and peak plasma levels for nadolol were lower, and the time to peak level was higher on hydralazine treatment, but no significance was achieved. Nadolol, however, was particularly poorly absorbed (8.5%) in this trial. Consequently, no conclusions can be drawn from these results, as small changes in absorption could have produced the effects seen. Acebutolol, and its major metabolite, diacetolol, were unaffected by hydralazine and although both acebutolol and hydralazine undergo acetylation during metabolism, acetylator status and pharmacokinetic changes were not correlated. Hydralazine would therefore appear to affect only those ~-blockers with a high degree of first-pass loss. Jack, D.B. et al.: Biopharmaceutics and Drug Disposition 3: 47 Oan-Mar 1982)

    0156-2703/82/0522-0013/0$01.00/0 ADIS Press INPHARMA 22 May 1982 13