Studies on the metabolism of diltiazem in man.

Abstract

The human urinary metabolites of diltiazem were analyzed by thin-layer chromatography (TLC) and gas chromatography-mass spectrometry. Diltiazem was metabolized by deacetylation, N-demethylation, O-demethylation and conjugation. Metabolite MA, N- monodemethyl -diltiazem, was identified as a new major metabolite in human urine, and four metabolites were identified as deacetyl-diltiazem (M1), deacetyl-N- monodemethyl -diltiazem (M2), deacetyl-O-demethyl-diltiazem (M4), deacetyl-N,O-demethyl-diltiazem (M6) which were known as rat urinary metabolites. Metabolite M2, M4 and M6 were converted in part to glucuronides and/or sulfates. Unchanged diltiazem and metabolite MA were determined in human plasma and urine by TLC-densitometry. Diltiazem and metabolite MA excreted in 24-h urine were 44.4 and 48.5% of the total unconjugated form, respectively. The mean plasma level of metabolite MA was approximately one-third of diltiazem level. On the basis of these findings, a probable metabolic pathway of diltiazem in man is presented.

N‐monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives.

“…It is also undergoing investigation for use as an antihypertensive and antiarrhythmic drug. Diltiazem is extensively metabolized by the liver with very little drug excreted unchanged in the urine (Sugihara et al, 1984). Major pathways of biotransformation include O-deacetylation, Ndemethylation, and O-demethylation.…”

Identification of the Atypical L-Type Ca2+ Channel Blocker Diltiazem and Its Metabolites As Ghrelin Receptor Agonists

“…Diltiazem is extensively metabolized (Rovei et al, 1980;Sugihara et al, 1984;Sugawara et al, 1988;Molden et al, 2000; see Fig. 1), and several of its metabolites also possess Ca 2ϩ channel-blocking activity (Schoemaker et al, 1987).…”

“…In addition, diltiazem has been shown to provide cardioprotection against ischemia/reperfusion injury in rats (Takeo et al, 2004), similar effects as have been noted for ghrelin and other GHSs (discussed above). Diltiazem is extensively metabolized, and several of these metabolites reach significant concentrations in humans (Rovei et al, 1980;Sugihara et al, 1984;Sugawara et al, 1988;Molden et al, 2000). Several metabolites of diltiazem also show binding activity at Ca 2ϩ channels, although all have lower affinity than diltiazem itself (Schoemaker et al, 1987).…”

“…We have not observed that diltiazem inhibits food intake and may even modestly stimulate food intake in rats (J.-N. Ma and E. S. Burstein, unpublished observations). The apparent lack of effect of long-term diltiazem administration on GH release or food intake could be interpreted as a lack of support for the role of ghrelin agonists in these effects; however it is probably more likely to be due to the primary effects of diltiazem (i.e., blockade of Ca 2ϩ influx), which may impair GH release (Lussier et al, 1988), and/or inadequate drug exposure (Rovei et al, 1980;Sugihara et al, 1984;Chaffman and Brogden, 1985), given its potency for activating GHSR1a receptors (current study) relative to its affinity for L-type Ca 2ϩ channels (Glossmann and Striessnig, 1990;Zobrist and Mecca, 1990), and is also consistent with our observations that diltiazem is a partial agonist at GHSR1a receptors. Diltiazem peak plasma concentrations as high as 152 ng/ml were reported in healthy adult male volunteers (Zelis and Kinney, 1982), which, depending upon the assay, is comparable with or significantly lower than the pEC 50 values reported here (Table 1).…”

“…Diltiazem is extensively metabolized (Rovei et al, 1980;Sugihara et al, 1984;Sugawara et al, 1988;Molden et al, 2000), and some of its metabolites, notably desacetyl diltiazem (M 1 ), reach plasma concentrations approaching 20 to 30% that of diltiazem itself in humans (Rovei et al, 1980;Sugihara et al, 1984 (Schoemaker et al, 1987). The M 2 metabolite, which we found to be significantly more potent and efficacious as a GHSR1a agonist than diltiazem, had approximately 10-fold lower activity in L-type Ca 2ϩ channel binding and functional assays than diltiazem (Schoemaker et al, 1987).…”