Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis.

Abstract

1 The pharmacokinetics, bioavailability and ECG response of verapamil was investigated in seven patients with liver cirrhosis and compared with six normal subjects, using stable labelled techniques whereby both the intravenous and oral dose are given simultaneously. 2 After intravenous administration, plasma concentrations were much higher in the patient group such that the total plasma clearance was reduced from a mean of 1258 ml/min in normals to 616 ml/min in the patient group (P less than 0.0025). The apparent volume of distribution nearly doubled (6.76 v 12.05 l/kg, P less than 0.025) and the terminal half‐life was prolonged four fold (3.7 v 14.2 h, P less than 0.001). 3 Given orally, the peak plasma concentration was higher and occurred earlier in the liver cirrhotic patients. The absolute bioavailability more than doubled (22.0% normals v 52.3% liver cirrhotics, P less than 0.001) and apparent oral clearance was reduced to only 20% of normal (6.38 v 1.30 l/min, P less than 0.001). 4 The delta P‐R interval in the patient group lagged behind the plasma concentration, in contrast to normal subjects. The maximum effect was much greater in the patients (15.4 v 41.6% increase, P less than 0.005) and persisted for a longer period of time. The slope of the plasma concentration‐response curve was the same as in normals after intravenous administration. Plasma protein binding remained unchanged. 5 It is recommended that in liver cirrhotic patients the intravenous dose of verapamil be halved and the oral dose decreased by a factor of five in order to prevent untoward effects. As well as a steady‐state plasma concentration will not be reached until approximately 2 days after the beginning of therapy.

Stereoselective first‐pass metabolism of highly cleared drugs: studies of the bioavailability of L‐ and D‐verapamil examined with a stable isotope technique.

“…There Eichelbaum et al, 1980Eichelbaum et al, , 1981Eichelbaum et al, a,b, 1984McAllister & Kirsten 1982). Previous studies have demonstrated that the same concentration of plasma verapamil following oral administration appeared to be two to three times less potent than that following i.v.…”

“…Somogyi et al (1982) proposed an equation to predict F of highly cleared drugs with reasonable accuracy. Since their original equation for verapamil was obtained from a limited number of subjects (n = 6), we added the present data as well as those obtained from patients with liver cirrhosis (Somogyi et al, 1981) In a recent study we demonstrated that the volume of distribution for the (-)-isomer was two times greater than that of the (+)-isomer . Therefore, the plasma concentration of the (+)-isomer was two times higher than that of the (-)-isomer following i.v.…”

“…where E is the hepatic extraction ratio, CLO is the apparent oral clearance and Q is liver blood flow (Rowland, 1972 (Eichelbaum et al, 1981) (Somogyi et al, 1981) were analyzed by least squares regression.…”

Prolonged half‐life of verapamil in a case of overdose: implications for therapy.

“…He was ventilated, and haemofiltered because of acidosis and a rising serum creatinine (maximum 424 g1M). His cardiac output was 8.6 1 min -1 (reference range 4-8), pulmonary capillary wedge pressure 21 mm Hg (6)(7)(8)(9)(10)(11)(12), and systemic vascular resistance 456 dyn s-1 m-2 (800-1200). He required dopamine, noradrenaline, and adrenaline to maintain systolic pressure.…”

Calcium-channel blockers and anaesthesia

“…Thus hepatic failure or decreased hepatic blood flow due to cardiac failure slows the metabolism of CCB. 21 The elimination of the inactivated compounds takes place mainly in the kidneys. However, chronic treatment prolongs the half-life because of saturation of hepatic first-pass effect, i.e., verapamil elimination half-life is extended to 6-9 hr.…”