Edoardo Spina

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance

Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance.

Phenotypic consistency in hydroxylation of desmethylimipramine and debrisoquine in healthy subjects and in human liver microsomes

The 2‐hydroxylation of desmethylimipramine (DMI) and the 4‐hydroxylation of debrisoquine (D) were studied in healthy subjects and in human liver microsomes. A single oral dose of DMI (25 mg) was given to 18 healthy subjects previously phenotyped with D (13 rapid and five slow hydroxylators). Urine was collected for 24 hr and DMI and total 2‐hydroxydesmethylimipramine (2‐OH‐DMI) levels were determined by HPLC. The urinary ratio DMI/2‐OH‐DMI correlated strongly (r = 0.92) with the urinary ratio of D to 4‐hydroxydebrisoquine (D/4‐OH‐D). The two hydroxydations were also studied in human liver microsomes from 10 different subjects. Formation rates of the hydroxylated metabolites correlated strongly (r = 0.869). Moreover, D competitively inhibited the 2‐hydroxylation of DMI. These findings suggest that both are hydroxylated by the same cytochrome P‐450 isozyme.

Inhibition of desipramine 2‐hydroxylation by quinidine and quinine

Urinary excretion of desipramine (DMI) and 2‐hydroxydesipramine (2‐OH‐DMI) after single oral doses of 25 mg DMI was investigated in seven rapid and three slow debrisoquin hydroxylators, before and after pretreatment with either quinidine or its diastereoisomer quinine. After treatment with 800 mg quinidine daily for 2 days, excretion of 2‐OH‐DMI decreased by 96% in rapid hydroxylators and 68% in slow hydroxylators. After treatment with 750 mg quinine/day for 2 days, excretion of 2‐OH‐DMI in rapid hydroxylators was 54% lower than during the control experiment, whereas in slow hydroxylators no significant changes in the excretion pattern were observed. Unchanged DMI constituted only a minor fraction of recovered drug and no significant changes in its recovery were observed in either phenotypic group after pretreatment with quinidine or quinine. Thus both quinidine and quinine decreased the excretion of 2‐OH‐DMI. At similar doses the effect of quinidine was much stronger than that of quinine, virtually transforming rapid hydroxylators into slow hydroxylators. The mechanism probably involves a stereoselective inhibition of DMI 2‐hydroxylation.

Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators

The disposition of a 25 mg single oral dose of desipramine was investigated in five rapid and four slow hydroxylators of debrisoquin before and during oral administration of 1200 mg cimetidine daily. AUC and elimination half‐life of desipramine increased during cimetidine administration in rapid but not in slow hydroxylators. This was the result of a decrease in overall clearance. The urinary recovery of 2‐hydroxydesipramine was significantly decreased in rapid hydroxylators during cimetidine administration. We conclude that cimetidine inhibits the metabolism of desipramine in rapid but not in slow hydroxylators.

Hydroxylation of desmethylimipramine: Dependence on the debrisoquin hydroxylation phenotype

The 2‐hydroxylation of desmethylimipramine (DMI) was studied in 14 healthy subjects previously phenotyped with respect to debrisoquin hydroxylation. After a single oral dose (25 mg), slow hydroxylators of debrisoquin had significantly lower total and metabolic clearances and longer plasma half‐lives of DMI and excreted less 2‐hydroxydesmethylimipramine than did rapid hydroxylators. These findings strengthen the hypothesis that the hydroxylations of debrisoquin and DMI may be under common enzymatic control.