Pharmacokinetics and Metabolism of Tiapamil

Abstract

The main pathways of biotransformation of tiapamil and basic pharmacokinetic information on the drug are presented and compared with those of verapamil. Both compounds are metabolized by similar pathways consisting mainly of N- and O-dealkylation. In man, the two main metabolites of tiapamil in blood and urine are the N-desmethyl derivative and the other secondary amine which has lost the dimethoxyphenethyl-moiety. Both metabolites have low pharmacological activity and do not contribute significantly to the effect of the parent drug. Analysis of single intravenous doses of 10 and 50 mg revealed that tiapamil has pharmacokinetic parameters very similar to those of verapamil, the total plasma clearances for both compounds being about 800 ml/min. Due to its somewhat smaller volume of distribution (twice body weight), tiapamil has a slightly shorter half-life of elimination from plasma [t½β] – 2.5 h – than does verapamil (4 h). On oral dosing, however, both drugs have substantially reduced bioavailability of about 20%, this being due to extensive first-pass metabolism rather than to incomplete absorption. Tiapamil plasma levels following intravenous infusion or multiple oral dosing may be predicted from basic pharmacokinetic parameters with reasonable accuracy. Neither tiapamil nor its metabolites tend to accumulate on repeated oral dosing of 200 mg tiapamil t.i.d. Though both tiapamil and verapamil are metabolized extensively, and only a small proportion of the dose is excreted unchanged, large differences exist with respect to the route of excretion. While the metabolites of verapamil are excreted largely (70% of the dose) in the urine after both intravenous and oral dosing, the metabolites of tiapamil are excreted largely in the faeces: 66% after intravenous administration and 90% after oral dosing.The following concept is proposed: Following oral administration, both drugs are rapidly and completely absorbed. They are subject to extensive first-pass metabolism involving gut and liver. While the metabolites of verapamil enter the systemic circulation and are excreted mainly by the kidneys, the metabolites of tiapamil are directly secreted into the bile and excreted in the faeces, thus bypassing the systemic circulation. This may have clinical consequences with respect to tolerance and safety of the drug.

Effect of a new calcium antagonist, tiapamil, in hypertension of the elderly.

“…Both drugs are extensively metabolized, but whereas the metabolites of verapamil appear in urine the metabolites of tiapamil are mainly excreted in the faeces. Tiapamil is 78% bound to plasma proteins, its half-life of elimination ranges from 2 to 3 h and its oral bioavailability from 20 to 30% (Wendt, 1982 (Cockcroft & Gault, 1976) (Borow et al, 1982). The validity of the results obtained with this method has already been published (Silas et al, 1980;Debru et al, 1981).…”

Excretion of tiapamil in breast milk.

“…The concentrations in (Wendt, 1982;Hartmann et al, 1983). t milk were less than half of those in plasma…”

“…Balansard et al, 1984;Rhomberg et al, 1983;Salorine et al, 1983). Its preclinical pharmacology and toxicology (Eigenmann et al, 1981a, b) and its pharmacokinetic characteristics in humans (Wendt, 1982;Hartmann et al, 1983;Hinderling et al, 1986) have been described. Tiapamil is a moderately lipophilic base with an octanol/water partition coefficient of 32 and a pKA of 8.4.…”

Tiapamil, Ro 11-1781, a Ca⁺⁺ Antagonist

“…Moreover, they can be ex posed without degradation to heat and light as well as artificial gastric or intestinal juice. They are compatible with pharmaceutical Investigation of the drug's metabolism [3] in vitro with rat liver microsomes and in vivo in rats, dogs and man led to the isolation of the three compounds, 5, 6 and 7.…”

“…A suspension of 9.90 g (25 mmol) of 17, 5.50 g K2CO3, 3.44 g (17 mmol) of 16 in 35 ml DMF was heated under stirring at 120 °C for 2 h. The mixture was poured into 250 ml of 5% NaCl solution, extracted 3 times with EtOAc. The organic solution was extracted 3 times with a 15% solution of tar taric acid.…”