Interaction of tertatolol with rifampicin and ranitidine pharmacokinetics and antihypertensive activity

Abstract

The interaction of the new beta-receptor antagonist tertatolol with rifampicin and ranitidine was investigated in ten patients with arterial hypertension (WHO stages I-II). They were treated orally with a single dose of tertatolol 5 mg alone and, after randomized allocation, with ranitidine 150 mg twice daily or rifampicin 600 mg once daily for 1 week each (tertatolol 5 mg was concurrently administered on the seventh day of the treatment phases). Following each therapeutic phase, circadian blood pressure values as well as kinetic parameters were obtained. On treatment with tertatolol alone, maximum plasma concentrations were 123.7 +/- 32.4 ng/ml (mean +/- SD) and were reached after 1.95 +/- 1.77 hours. The tertatolol elimination half-life was 9.0 +/- 7.1 hours. Coadministration of ranitidine did not significantly alter the kinetic parameters and antihypertensive effect of tertatolol. Rifampicin, however, decreased the maximum plasma levels of tertatolol to 80.6 +/- 18.5 ng/ml and markedly shortened the elimination half-life to 3.4 +/- 2.6 hours (p less than 0.01 compared with tertatolol alone). Urinary excretion of parent tertatolol and unchanged 4-hydroxy tertatolol was decreased under rifampicin, and a tendency to a reduction in the effect of tertatolol on circadian blood pressure values was observed. Twenty-four hours after administration, the heart rate in those patients on tertatolol alone (68 +/- 6 beats/min) was lower than in those on tertatolol plus rifampicin (74 +/- 7 beats/min). In conclusion, a pronounced pharmacokinetic interaction, with a limited consequence in terms of pharmacodynamic effects, was found in the present study when tertatolol was administered with rifampicin, but not with ranitidine.

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

“…RIF decreased talinolol AUC by 21% after intravenous and by 35% after oral administration, probably through increased P-gp mediated excretion [117]. For teratrolol, a 35% decrease of teratrolol AUC was caused by RIF [118]. Single oral dose RIF reduced the mean oral bioavailability of nifedipine to 36%, decreased the t 1/2 , and increased the total clearance, but had no effect on t max and apparent V d [119].…”

Predicting Interactions between Rifampin and Antihypertensive Drugs Using the Biopharmaceutics Drug Disposition Classification System

“…However, rifampin interaction studies in the literature report the results for two antihypertensive drugs approved in Europe and South Korea, respectively—tertatolol and fimasartan—that we determined to be BDDCS classes 1 and 4, respectively. For tertatolol, as would be expected, rifampin coadministration resulted in decreased drug concentrations 27 . For fimasartan, rifampin caused an increase in exposure due to inhibition of hepatic uptake for this drug primarily eliminated into the bile 39 …”

“…Therefore, we also summarized the information on these drugs in Table 2. Nilvadipine and tertatolol are extensively metabolized, and coadministration with rifampin reduced their exposure to 3.45% and 42.7%, respectively 27, 30 . Talinolol and fimasartan undergo a low extent of metabolism and are substrates of transporters such as P‐gp.…”

“…Previous case reports and human pharmacokinetic and pharmacodynamic studies reported the interactions between rifampin and antihypertensive drugs. [4][5][6][7][8][9][10][11][12][13][14][15][16][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] However, to our knowledge, no systematic summary or predictions of these interactions have been published. Thus we used the Biopharmaceutics Drug Disposition Classification System (BDDCS) to predict the direction and relative extent of both transporterbased DDIs and metabolic interactions.…”

Side Effects of Ranitidine

“…Similarly, no interactions were shown with atenolol, a {3-blocking drug which is not metabolised and is mainly eliminated via the urine (Mutschler et al 1984;Spahn et al 1983). The pharmacokinetics and antihypertensive effect of a single dose of tertatolol were not altered after a I-week ranitidine treatment in 10 patients with arterial hypertension (Kirch et al 1990).…”