Altered diltiazem metabolism in the neonatal rabbit following intra-uterine chronic exposure to diltiazem

Abstract

1. Diltiazem undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-demethyldiltiazem (MA) are two of the main basic metabolites of diltiazem that retain pharmacological activity. This drug impairs its own metabolism after chronic administration in the adult patient. The study examines the possibility that intra-uterine exposure following chronic maternal therapy with DTZ from mid-gestation to term also impairs DTZ metabolism of its offspring. 2. DTZ was incubated in homogenates from liver, lung, brain and gut and in the whole blood of animals whose mothers were exposed to chronic treatment with diltiazem or unexposed (placebo). DTZ and its metabolites were assayed by HPLC. 3. DTZ deacetylase activity observed in liver, lung and brain homogenates from 1-, 8- and 16-day-old rabbits was significant lower in exposed animals. In gut homogenates, this age-dependent effect was not so clear. This inhibition could not be detected in any organ of 30-day-old rabbits. On the other hand, the activity observed in whole blood was not altered by intra-uterine chronic exposure to DTZ. 4. DTZ demethylase activity showed no differences in tissue homogenates and in whole blood from exposed compared with the unexposed rabbit. 5. In conclusion, the findings suggest that intra-uterine chronic exposure to DTZ has a large and prolonged effect on newborn metabolism deacetylase activity compared with the unexposed rabbit.

Investigation of diltiazem metabolism in fish using a hybrid quadrupole/orbital trap mass spectrometer

“…N-Desmethyl diltiazem (M1) and desacetyl diltiazem (M2) are the two main diltiazem metabolites that retain pharmacological activity. [34] M1 and M2 were also the main metabolites of diltiazem detected in fish tissues in this study. While CYP2D6 performs O-desmethylation of diltiazem in mammals, [12] the CYP2D sub-family is not present in fish, [35] which explains why the M1 and M3 metabolites were identified as products of desmethylation at the N atom only.…”

“…In mammals, diltiazem undergoes extensive metabolism in hepatic and extra‐hepatic tissues. N ‐Desmethyl diltiazem (M1) and desacetyl diltiazem (M2) are the two main diltiazem metabolites that retain pharmacological activity . M1 and M2 were also the main metabolites of diltiazem detected in fish tissues in this study.…”

Penetration of diltiazem into breast milk and its pharmacokinetics in the lactating rabbit

“…The chemical breakdown of DTZ, M1 and MA and two separate studies on the stability of M1 and MA in whole milk and mammary tissue homogenates were assessed as described by Fraile et al (2001a). Brie¯y, the chemical breakdown of DTZ, MA, and M1 was assessed in vials containing the same composition but inactivated by heat (5 min at 75 8C).…”

“…Demethylation and deacetylation of DTZ in mammary tissue homogenates or in whole milk were assessed in the presence or absence of an NADPH-regenerating system, respectively as described by Fraile et al (2001a). Incubations were conducted in glass vials in an oscillating water bath (75 oscillations min ¡1 ) at 37 8C for 10 min in air.…”