Pharmacokinetics and metabolism of diltiazem in rats: comparing single vs repeated subcutaneous injections in vivo

Abstract

The objective of the study was to determine the effect of repeated administration on the pharmacokinetics and metabolism of diltiazem (DTZ) using an in vivo rat model. Male SD rats (n = 6-10 per group) weighing 350-450 g were used. Each rat received either a single 20 mg/kg dose of DTZ by subcutaneous (s.c.) injection or 5 mg/kg s.c. twice daily for five doses. Plasma concentrations of DTZ and its major metabolites were determined by HPLC for up to 8 h. Compared with the single dose, repeated administration resulted in higher dose normalized plasma concentrations of DTZ (AUC 26.4+/-14.2 vs 13.9+/-11.5 microg-h/ml), longer apparent half-life (t(1/2) = 12.5+/-14.6 vs 3.7+/-1.4 h) and lower systemic clearance (CL = 1.1+/-1.0 vs 2.9+/-2.7 l/h/kg). Higher dose normalized plasma concentrations, longer t(max), but shorter apparent t(1/2) of the major metabolites were observed following the repeated administration. The results also suggest that possible binding of DTZ may occur at the site of injection when administered subcutaneously in the higher dose.

Pharmacokinetics and Hemodynamic Effects of Diltiazem in Rats Following Single vs Multiple Doses In Vivo#

“…1). As has been reported previously, M2 was the most abundant metabolite in SD rats, followed by M1 and then MA, and M2 and MA accumulated more than DTZ and M1 following repeated administration [18]. Following the single 20 mg/kg subcutaneous injection, the observed SBP fell significantly (p < 0.05) on average from 138 ± 4 to 125 ± 3 mmHg (-9.4%), DBP from 105 ± 3 to 78 ± 4 mmHg (-26%), and HR from 442 ± 12 to 396 ± 7 bpm (-10%).…”

“…Similarly based on the estimated Emax and Emin calculated from the Inhibitory Emax model (Table 1), the reduction for DBP was 50% vs 33 % for the SBP. The much greater hemodynamic effects observed previously were attributed mainly to the 5 times higher maximum plasma concentrations of DTZ attained after the direct intra-arterial injections [18,21].…”

“…While details of the pharmacokinetic data analysis and interpretation have been recently published [18], the hemodynamic effects and their relationships with pharmacokinetics of DTZ and its metabolites have not been reported; there- fore only the plasma concentration-time profiles are shown here (Fig. 1).…”

“…More recently, we have shown that repeated administration of DTZ reduced systemic clearance of DTZ. The concentrations of the active metabolites such as MA, M1 and deacetyl-N-monodesmethy DTZ (M2) were similar to or higher than the concentrations after single dose [18]. Thus, it is unlikely the reduced DTZ clearance is attributed to inhibition of the P-450s catalyzing formation of these active metabolites.…”

Comparing pharmacokinetics and metabolism of diltiazem in normotensive Sprague Dawley and Wistar Kyoto rats vs. spontaneously hypertensive rats in vivo

“…Previous studies have shown that signifi cant hemodynamic effect was obtained at this dosage, and that the pharmacokinetics and pharmacodynamics of DTZ could be adequately characterized following this regimen (11,17) .…”