Attenuation of rifampicin-induced theophylline metabolism by diltiazem/rifampicin coadministration in healthy volunteers

Summary

On the basis of reports that diltiazem binds to the hepatic microsomal enzymes and inhibits the metabolism of coadministered drugs, we investigated the effect of a 240 mg daily dose of the calcium channel blocker for a week on theophylline metabolism in 8 healthy male volunteers aged 20–24 years and weighing 56–68 kg.

None of theophylline half-life (9.7 h), volume of distribution (0.514 l·kg⁻¹) and total clearance (0.63 ml·min⁻¹·kg⁻¹) after pretreatment differed from the respective control value of 9.5 h, 0.519 l·kg⁻¹ and 0.65 ml·min⁻¹·kg⁻¹.

In 6 of the volunteers, 600-mg daily dose of rifampicin for a week induced theophylline metabolism. The control half-life of the bronchodilator (9.6 h) was reduced to 5.5 h and its total clearance (0.64 ml·min⁻¹·kg⁻¹) increased to 1.22 ml·min⁻¹·kg⁻¹. There was no change in volume of distribution.

In these 6 volunteers, intake of diltiazem (240 mg daily), concurrently with rifampicin for a week, significantly elevated theophylline half-life to 6.2 h as well as reduced its clearance to 1.03 ml·min⁻¹·kg⁻¹. The volume of distribution did not change. Furthermore, diltiazem-induced absolute fall in theophylline clearance correlated significantly with its post-rifampicin value (r=0.895).

It is suggested that diltiazem has no effect on theophylline metabolism in non-induced subjects. However, rifampicin-induced metabolism of the bronchodilator could be attenuated by diltiazem when the two drugs are given concurrently.