Verapamil disposition‐effects of sulphinpyrazone and cimetidine.

Abstract

The effects of separate 7 day pretreatments with sulphinpyrazone (800 mg daily) and cimetidine (1 g daily) on the disposition of (+/‐)‐ verapamil have been examined in eight healthy volunteers (four male, four female). Each subject received single oral (80 mg) and intravenous (0.15 mg/kg) doses of verapamil on different occasions before and after each pretreatment. Following sulphinpyrazone pretreatment, verapamil apparent oral plasma clearance (CLpo) increased from 4.27 to 13.77 l h‐ 1 kg‐1 (s.e. mean 0.51‐ANOVA) (P less than 0.001); CL increased from 1.05 to 1.20 l h‐1 kg‐1 (s.e. mean 0.05) (P less than 0.05) and Fpo decreased from 27 to 10% administered dose (s.e. mean 2) (P less than 0.001). Vss and t1/2,z were unchanged. There was no sex difference for any dispositional parameter in the control phase, but the increase in CLpo following sulphinpyrazone pretreatment was more marked in males (4.04 to 17.33 l h‐1 kg‐1) than in females (4.49 to 10.21 l h‐1 kg‐1) (s.e. mean 0.72) (P less than 0.01). There was no significant change in any verapamil disposition parameter following cimetidine pretreatment. Verapamil unbound fraction in plasma was 0.157 (s.e. mean 0.001, n = 40). There was no alteration in verapamil plasma protein binding associated with increasing verapamil concentration (25‐250 micrograms l‐ 1) or addition of sulphinpyrazone (50‐500 mg l‐1) or cimetidine (0.5‐5 mg l‐1). The results suggest that sulphinpyrazone induces the metabolic clearance of (+/‐)‐verapamil with a sex difference in the response.(ABSTRACT TRUNCATED AT 250 WORDS)

HepaRG Cells as an in Vitro Model for Evaluation of Cytochrome P450 Induction in Humans

“…The in vivo induction is represented by the decrease in AUC for a CYP3A probe drug, administered before and after treatment with the inducing agent. The in vivo probes used for the correlation were midazolam for rifampicin (Backman et al, 1996a(Backman et al, , 1998, phenytoin (Backman et al, 1996b), carbamazepine (Backman et al, 1996b), and hyperforin (St. John's wort) (Wang et al, 2001); verapamil for phenobarbital (Rutledge et al, 1988) and sulfinpyrazone (Wing et al, 1985); terfenadine for troglitazone (Loi et al, 1998); and triazolam for dexamethasone (Villikka et al, 1998). These probe drugs are moderate or high clearance drugs (Greenblatt et al, 1998;Wong et al, 1998;Lin, 2006), and the clearance and bioavailability are dependent on CYP3A4 metabolism.…”

The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris.

“…Thus, propranolol (Schneck & Pritchard, 1981) and lignocaine (Tucker et al, 1982) oxidation are inhibited by propranolol but N-dealkylation (one of the major routes of verapamil metabolism (Eichelbaum et al, 1979)) is affected less readily than aromatic hydroxylation. Furthermore, although the metabolism of verapamil is induced by sulphinpyrazone, it is unaffected by cimetidine, a potent inhibitor of the metabolism of many drugs (Wing et al, 1985). In contrast, verapamil did appear to influence the pharmacokinetics of propranolol during continous therapy.…”

Clinical Relevance of Cimetidine Drug Interactions

“…There was no significant change in the time needed to attain tmax, suggesting that nifedipine absorption was unaltered. In contrast, ranitidine 300mg daily had no significant effect on the AVC or Cmax of single or Mooy et al (1985); Smith et al (1984); Wing et al (1985) Abbreviations: C = serum/blood/plasma drug concentration; AUC = area under the concentration-time curve; F = bioavailabillty.…”

“…Several investigators have reported that cimetidine had no significant effect on the pharmacokinetics of orally or intravenously administered verapamil; its bioavailability, volume of distribution, Cmax, half-life and clearance were unaltered during coadministration of cimetidine 400 to 1200 mgjday in healthy volunteers (Abernethy et al 1985;Mooy et al 1985;Wing et al 1985). However, Smith et al (1984) noted that cimetidine increased the bioavailability ofverapamil from 26 to 49%, while other pharmacokinetic parameters remained unaltered.…”