EUROPEAN JOURNALOF DRUOMBTABOUSM AND PHARMACOKINETICS, 1993, VoL 18,No.2, pp. 199-206 Pharmacokinetics and metabolism of diltiazem in healthy males and females following a single oral dose F o' C ESCO--:l C 2 2,4 1 P.K.. YEUN , . PR 're,. HADDAD, TJ. MONTAGUE ,C. McGREGOR, 3 1 1 1 2 M.A. QUILLIAM ,M. XEI ,R. LI ,P. FARMER and G.A. KLASSEN lColiege of Pharmacy, Dalhousie University, Halifax, Nova Scotia, Canada 2Division of Cardiology, Victoria General Hospital, Halifax, Nova Scotia, Canada 31nstitllJe of Marine Biosciences, National Research Council of Canada, Halifax, Nova Scotia, Canada Receivedforpublication: August 3,1992 Keywords: Diltiazem, pharmacokinetics, metabolism, calcium antagonist SUMMARY Plasma concentrations and urinary excretion of DTZ and its metabolites were dctcrmincd in 20 healthy voluntccn (10 males and 10 females) after they had each been given a single oral 90 DI8 dose of DTZ. DTZ and six of its metabolites which included N-monodcsmethyl DTZ (MA), dcacctyl DTZ (MI), dcacctyl N-monodcsmcthyl DTZ (M1), dcacetyl O-dcsmethyl DTZ (M4) and dcacctyl DTZ N-oxide (MINO) and dcacctyl N,O-didcsmcthyl DTZ (M6>' determined by a sensitive andspecific HPLC I818Y. The major metabolitcameasurable in the plasma of all the voluntccrl were MAo MI, and M1. The taminal half-lives (t1l1) of MI and M1 were coDsidcrably longer than those of DTZ and MA. Less than 59f1 of the cIosc was excreted as unchanged DTZ in the urine over the 24 h period. The maj(X" urinary metabolite was MAo followed by M6, M20 and then MI. Except for' the urinary excretioo of M4 there were no statistically significant differences in any of the pharmacokinctic parametcrll between the males and the females. The mean 24 h urinary recovery of M4 was higher in the males than in the females (P < 0.05). there wcrc larJ'C inter-individual variations in the plasma concentrations and urinary excretion of DTZ and its metabolites with some parameten differing by more than 2O-fold. In addition. O-dcsmcthyl DTZ (Mx) and N,O-didcsmcthyl DTZ (MB) wa'C identified u two other major urinary metabolitca. INTRODUCTION Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina, hypertension and cardiac The material was presented, in pert, at the 3rd International ISSX meeting. Amsterdam, The Netherlands.June 1991. 4Present oddress: Director. Division of Cardiology. Univer- sity of Alberta Hospitals, Edmonton, Alberta. Canada. PUoSe send reprint requuts to: Dr Pollen K.F. Yeung, Col- lege of Pharmacy, Faculty of Health Professions, Dalhousie University, Halifax. Nova Scotia. Canada B3H 3J5. anbytbmias (1-3). It is extensively metabolized in humans' (Fig. 1) via deacetylation, N-demetbyJation. O-demetbylation. N-oxidatioo and oxidative deamina- lion. yielding a host of basic and acidic metabolites some of which have potent phannacological activities (4-8). It bas been shown that the coronary vasodilat- ing potencies of deacetyl DTZ (MI) and N-monode- smetbyl DTZ' (MA) were approximatelySO% and 20%. respectively. that of DTZ (6). However. in inhi- biting platelet aggregation and uptake of adenosine by erythrocytes. MI and deacetyl O-desmetbyl DTZ (M4) were considerably more active than the parent dmg DTZ (9. 10). There are large inter-individual vari-