Effetto della funzionalità renale ed epatica sulla cinetica di disposizione dei farmaci e le interazioni farmacocinetiche conseguenti ad inibizione del metabolismo

SUMMARY This study analyzes the effect of renal and hepatic insufficiency on metabolic drug disposition and drug-drug interactions. In particular, we evaluated: 1.the effect of renal failure on hepatic drug metabolism; 2.the effect of liver dysfunction on pharmacokinetic interactions consequent upon inhibition of drug metabolizing enzymes. 1- Background and Objectives: The effect of chronic renal failure (CRF) on the pharmacokinetics of lidocaine, a drug cleared almost exclusively by hepatic metabolism, has thus far only been evaluated in patients undergoing regular hemodialysis. This study had 2 objectives: (a) to investigate the effect of CRF on the pharmacokinetics of lidocaine in both patients undergoing hemodialysis and patients not undergoing hemodialysis and (b) to test the effects of plasma from the patients examined and of lidocaine metabolites possibly accumulated in vivo on lidocaine biotransformation in vitro. Methods: In a clinical investigation we studied the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), after intravenous injection of 1 mg/kg lidocaine in 15 healthy volunteers (creatinine clearance [CLcr] >80 ml/min · 1.73 m2), 10 subjects with moderate renal insufficiency (CLcr between 30 and 60 ml/min · 1.73m2), 10 subjects with severe renal insufficiency (CLcr<30 ml/min · 1.73 m2), and 10 functionally anephric patients undergoing long-term hemodialysis. In experiments in vitro we determined the effects of plasma and GX on the formation rate of the primary lidocaine metabolite, MEGX, by use of human liver microsomes. Results: In patients not undergoing hemodialysis, lidocaine kinetic parameters were altered in proportion to the degree of renal function impairment, but only in patients with severe renal insufficiency were differences statistically significant: clearance was about half that of control subjects (mean ± SD, 6.01 ± 2.54 ml/min · kg versus 11.87±2.97 ml/min · kg; P<0.001), and half-life was approximately doubled (4.55 ± 1.71 hours versus 2.24 ± 0.55 hours, P < 0.001). No such alterations were observed in patients undergoing regular hemodialysis, whose values were similar to those of the control group. The steady-state volume of distribution and MEGX levels were independent of renal function, whereas GX levels were more than double those of control subjects (P<0.05) in all CRF groups. No inhibitory effect of plasma was observed, for any of the subjects examined, on lidocaine biotransformation in vitro. GX was found to be a competitive inhibitor, but its apparent inhibition constant value (52 ± 6 µmol/l) was 2 orders of magnitude higher than its concentrations in vivo. Conclusions: Our in vivo findings have both clinical and methodologic implications: (a) Lidocaine dose adjustment may be required in patients with severe renal insufficiency who are not receiving hemodialysis. (b) Results of studies evaluating the effect of CRF on metabolic drug disposition are not of general validity, unless both patients undergoing hemodialysis and patients not undergoing hemodialysis have been examined. Our in vitro observations exclude that impairment of lidocaine disposition is the result of direct inhibition of metabolizing enzymes by accumulated metabolites or uremic toxins. Alternative mechanisms, suggested by the results of recent in vitro studies, are discussed. 2- Background and Objectives: In vivo inhibition of cytochrome P450 (CYP) 1A2 by the reversible inhibitor fluvoxamine causes a reduction in the clearance of CYP1A2 substrates, the magnitude of which decreases in proportion to the degree of liver dysfunction, regardless of the clearance characteristics (flow-dependent or capacity-limited) of the drug involved. A main question remains to be addressed in order to assess whether this is a general phenomenon, i.e. whether the magnitude of the inhibitory effect is dependent on liver functional status irrespective the mechanism (reversible or irreversible) of CYP inhibition. In order to resolve this question, we evaluated the effect of liver cirrhosis on the inhibition of the metabolic disposition of quinine, a probe of CYP3A, by the mechanism-based, quasi-irreversible inhibitor erythromycin. Methods: The study was carried out in 10 healthy volunteers and 20 cirrhotic patients, 10 with mild (Child grade A) and 10 with severe (Child grade C) liver dysfunction, according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 5 days; in the other phase they received 600-mg doses of erythromycin ethylsuccinate, 8 h apart, for 5 days. On day 2 of both phases, quinine sulphate (500 mg) was administered orally 1 h after the morning erythromycin dose. Concentration of quinine and its metabolite 3-OH-quinine were measured by HPLC in plasma and urine up to 96 h. Free quinine concentration was determined in all plasma samples by ultrafiltration. Results: Erythromycin co-administration significantly reduced quinine clearance in healthy subjects and in patients with mild liver dysfunction (by 33% and 30%, respectively), whereas it had virtually no effect on quinine clearance in patients with severe liver functional impairment. Erythromycin also caused a marked increase in free quinine fraction, particularly in Child class C cirrhotics, in which unbound fraction was almost doubled. At variance with total quinine clearance, unbound clearance was significantly reduced (by 35%) also in patients with severe cirrhosis. Total and unbound formation clearances of 3-OH-quinine were reduced to similar extents (about 60% and 75%, respectively) in the three study groups. Conclusions: The effect of erythromycin on total quinine clearance is the result of two opposing actions: inhibition of the intrinsic metabolic activity of the liver and increase in free quinine concentration which, in Child C cirrhotics, is such as to completely mask the inhibition of intrinsic clearance. The observation that unbound quinine clearance and 3-OH-quinine formation clearance are inhibited to a very similar extent in controls and cirrhotic patients indicates that, unlike reversible inhibitors, the effect of irreversible inhibitors does not depend on liver functional status.