Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects

Abstract

1 The kinetics of diltiazem were investigated in ovariectomized (ovx) non-pregnant and intact late pregnant anaesthetized rats following a bolus i.v. injection (2mg kg-') and during a 180 min i.v.infusion (50 fig kg-' min-' and 100 yg kg-min '). Uterine contractions, mean blood pressure and heart rate were measured in the non-pregnant rats. 2 Measurement of serum diltiazem concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: volume of distribution area (V(area)) -256 ± 46 ml; rate constants k,2 -0.46 ± 0.10min-'; k2, -0.09 ± 0.01 min-'; ke1 -0.13 ± 0.03 min-'; elimination clearance -3.2 ± 0.3 mlmin-'; distribution t, (to) -1.4 ± 0.3 min; elimination t, (tio) -61.2 ± 13.0 min. In pregnant rats, a biexponential decay was also observed with similar parameters to those in non-pregnant animals except for markedly increased V(ara) -1004 ± 184 ml; k.1 -0.54 ± 0.16 min-' and elimination clearance -14.8 ± 2.3 mlmin-'.3 Measurement of serum diltiazem concentrations during infusion yielded the following parameters in non-pregnant ovx rats: V(SS) -79 ± 10 ml; rate constants k,2 -1.02 ± 0.21 min-'; k2, -0.03 ± 0.01 min-'; ke1 -0.39 ± 0.06 min '; elimination clearance -7.8 ± 1.2 ml min '. In pregnant rats a marked increase was observed in kel -1.25 ± 0.38 min-' and elimination clearance -36.4 ± 13.8 ml min 4 An immediate reduction in uterine contractions, mean blood pressure and heart rate was observed after bolus i.v. injection of diltiazem with a return towards control values as serum diltiazem concentrations declined. There were significant correlations between the inhibition of the 3 parameters and the log serum concentrations of diltiazem. Serum concentration-response curves indicated IC_, values of 0.5 jpg ml-' for inhibition of uterine contractions, 0.7 pg ml-' for reduction in blood pressure and 1.2 Fg ml-' for reduction in heart rate. There were maintained reductions in the integral of uterine contractions, mean blood pressure and heart rate during infusion. 5 The metabolite desacetyldiltiazem was rarely detected after i.v. bolus injection and was not found in 5/13 rats infused with diltiazem, yet significant inhibition of uterine contractions was observed in all rats. Diltiazem was 3.2 fold more potent than desacetyldiltiazem as an inhibitor of contractions of the rat isolated uterus. 6 These findings indicate that the inhibition of uterine contractions is due to a direct action of diltiazem, and not the metabolite desacetyldiltiazem, and suggest only a slight selectivity for uterine inhibition compared to cardiovascular effects.

Tolerance to cromakalim in the rat uterus in vivo

“…It was suggested that the relaxant action in the uterus may be exerted by a selective action on K+-channels in pacemaker cells 1 Author for correspondence. (Hollingsworth et al, 1987), a proposal supported by other workers (Quast, 1987).…”

“…This effect is seen both in non-pregnant and pregnant rats. Previously, cromakalim was shown to be a potent uterine relaxant in vitro (Hollingsworth et al, 1987;Small et al, 1988), although in these studies only tissue from term pregnant rats was used. Like other uterine smooth muscle relaxants, cromakalim can produce a complete and immediate inhibition of spontaneous contractions.…”

“…The potency and relaxant profile of cromakalim is similar in the uterus as in other isolated tissues and cromakalim is antagonized by several K+-channel blockers . However, cromakalim produced only a small hyperpolarization and no increase in 86Rb+ (Hollingsworth et al, 1987) or 42K' efflux in uterus. It was suggested that the relaxant action in the uterus may be exerted by a selective action on K+-channels in pacemaker cells 1 Author for correspondence.…”

“…Intrauterine pressure, blood pressure and heart rate were measured in conscious unrestrained rats and recorded on a polygraph (Grass Instruments, Quincy, MA, U.S.A.) as described previously (Downing et al, 1987;. Uterine contractions were quantified by integrating the area under the pressure curve above basal resting pressure using a 7P10 integrator.…”

“…Cromakalim is also a relaxant of isolated uterus from term pregnant rats (Hollingsworth et al, 1987;Small et al, 1988). The potency and relaxant profile of cromakalim is similar in the uterus as in other isolated tissues and cromakalim is antagonized by several K+-channel blockers .…”