Diltiazem pharmacokinetics

Winship LC, McKenney JM, Wright JT Jr, Wood JH, Goodman RP. The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics. Pharmacotherapy 1985 5(1) 16-19. 

Matera MG, De Santis D, Vacca C, Fid F, Romano AR, Marrazzo R, Maimo E. Quinidine-diltiazem pharmacokinetic interaction in humans. Curr TherRes ( 9S6) 40, 653-6. 

Drda KD, Bastian TL, Self TH, Lawson J, Lanman RC, Burlew BS, Lalonde RL. Effects of debrisoquine hydroxylation phenotype and enzyme induction with rifampin on diltiazem pharmacokinetics and pharmacodynamics. Pharmacotherapy (1991) 11, 278,... 

Renal function impairment The pharmacokinetics of diltiazem and verapamil in patients with impaired renal function are similar to the pharmacokinetic profile of patients with normal renal function. However, caution is still advised. Nifedipine s plasma concentration is slightly increased in patients with renal impairment. Nicardipine s mean plasma concentrations, AUC and maximum concentration were about 2-fold higher in patients with mild renal impairment. 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

The most common interactions with SSRIs are pharmacokinetic interactions. For example, paroxetine and fluoxetine are potent CYP2D6 inhibitors (Table 30-4). Thus, administration with 2D6 substrates such as TCAs can lead to dramatic and sometimes unpredictable elevations in the tricyclic drug concentration. The result may be toxicity from the TCA. Similarly, fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension. Other SSRIs, such as citalopram and escitalopram, are relatively free of pharmacokinetic interactions. The most serious interaction with the SSRIs are pharmacodynamic interactions with MAOIs that produce a serotonin syndrome (see below). 

Dixit AA, Rao YM. Pharmacokinetic interaction between diltiazem and tolbutamide. Drug Metabol Drug Interact 1999 15(4) 269-77. 

The effects of co-administration of oral diltiazem, a potent inhibitor of CYP3A, on the pharmacokinetics of lovastatin have been evaluated in a randomized study in 10 healthy volunteers (10). Lovastatin is oxidized by CYP3A to active metabolites. Diltiazem significantly increased the oral AUC and maximum serum concentration of lovastatin, but did not alter its half-life. The magnitude of the increase of plasma concentration of lovastatin suggested that caution is necessary when coadministering diltiazem and lovastatin. 

In another study by the same investigators, 10 healthy volunteers were randomized in a two-way, crossover study either to oral lovastatin or to intravenous diltiazem followed by oral lovastatin. Intravenous diltiazem did not significantly affect the pharmacokinetics of lovastatin (oral AUC, Cmax, tmax, or half-life), suggesting that the interaction does not occur systemically and is primarily a first-pass effect (11). Drug interactions with diltiazem may therefore become evident when a patient is changed from intravenous to oral dosing. 

BottigerY Sawe J, Brattstrom C, et al. Pharmacokinetic interaction between single oral dose of diltiazem and sirolimus in healthy volunteers. Cli Pharmacol 2001 69 32-40. 

Wilding, I., Hardy, J., Maccari, M., Ravelli, V., and Davis, S., Scintigraphic and pharmacokinetic assessment of a multiparticulate sustained release formulation of diltiazem, International Journal of Pharmaceutics, Vol. 76, No. 1-2, 1991, pp. 133-143. 

Pharmacokinetics Verapamil and diltiazem are absorbed after oral administration. Verapamil is extensively metabolized by the liver thus, care should be taken in administration of this drug to patients with hepatic dysfunction. 

Lamberg TS, Kivisto KT, Neuvonen PJ. Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther 1998 63(6) 640-5. 

There are two groups dihydropyridines and diltiazem/verapamil. Both groups are metabolized by the CYP3A family of isoenzymes (especially CYP3A4), which are the sites of many of the pharmacokinetic interactions involving this class. Some drugs are substrates for P-gp. 

Deslandes A, Camus F, Lacroix C, Carbon C, Farinotti R. Effects of nifedipine and diltiazem on pharmacokinetics of cefpodoxime following its oral administration. Antimicrob Agents Chemother 1996 40(12) 2879-81. 

However, some calcium channel blockers have pharmacokinetic interactions diltiazem, verapamil, nicardipine, and amlodipine increase ciclosporin concentrations, whereas nifedipine, felodipine, and isradipine do not (SED-14, 604) (SEDA-21, 210) (SEDA-21, 212)... 

Studies of the effects of diltiazem on the pharmacokinetics of digoxin have yielded variable results. In one study, diltiazem reduced the steady-state total body clearance of beta-acetyldigoxin in 12 healthy men, perhaps because of reduced renal and non-renal clearances (SEDA-10, 145). In some studies diltiazem 120-240 mg/day increased steady-state plasma digoxin concentrations by about 20-40% (SEDA-14, 146) (239), although not in other... 

Diltiazem abolishes the acute renal hypoperfusion and vasoconstriction induced by ciclosporin in renal transplant patients. Plasma endotheUn-1 may be a mediator of ciclosporin-induced renal hypoperfusion, but is not affected by diltiazem (26). This interaction has been confirmed with a new microemulsion formulation of ciclosporin in nine patients with renal transplants who took diltiazem 90-120 mg bd for 4 weeks (27). Diltiazem caused a 51% increase in the AUC of ciclosporin and a 34% increase in peak concentration, without altering the time to peak concentration. However, the ciclosporin microemulsion did not significantly affect the pharmacokinetics of diltiazem. 

Co-administration of diltiazem with methylprednisolone increased plasma concentrations of methylprednisolone and its adrenal suppressant effects in nine healthy volunteers (29). Care should be taken when these two drugs are co-administered for a long period, even if the clinical relevance of this pharmacokinetic interaction still needs to be evaluated. 

The pharmacokinetic interaction of a single oral dose of diltiazem 120 mg with a single oral dose of sirolimus 10 mg... 

Asberg A, Christensen H, Hartmann A, Carlson E, Molden E, Berg KJ. Pharmacokinetic interactions between microemnl-sion formulated cyclosporine A and diltiazem in renal transplant recipients. Eur J Clin Pharmacol 1999 55(5) 383-7. 

Pharmacokinetic interactions of moricizine and diltiazem in healthy volunteers. J Chn Pharmacol 1996 36(12) 1161-8. 

In 18 healthy subjects, in a randomized, crossover study of the pharmacokinetics of a single oral dose of sirolimus 10 mg, a single dose of diltiazem 120 mg, and the combination, diltiazem increased exposure to sirolimus, presumably by inhibiting its first-pass metabolism (13). 

Jones TE, Morris RG. Pharmacokinetic interaction between tacrolimus and diltiazem dose-response relationship in kidney and liver transplant recipients. Clin Pharmacokinet 2002 41(5) 381-8. 

Tada H, Yanagiwara S, Ito K, Suzuki T. Role of diltiazem on tacrolimus pharmacokinetics in tacrolimus-induced nephrotoxic rats. Pharmacol Toxicol 1999 84 241 -246. 

Example Diltiazem hydrochloride (Cardizem) Route PO/IV Pregnancy Pharmacokinetic Well category C absorbed from GI tract. PB 70%-80% Undergoes first-pass metabolism in liver. Metabolized in liver excreted in urine not removed by hemodialysis... 

Diltiazem was shown to exhibit dose dependent (30 mg - 120 mg administrated orally, three times a day) nonlinear pharmacokinetics (43) when administered to healthy individuals. The nonlinearity of diltiazem area under the curve (AUC) is a result of dose dependent first pass metabolism and is not reflected in the elimination half-life which is the same regardless of dose. The mean apparent oral clearance (44) and half-life of diltiazem following chronic oral therapy was 20.9 mL/min/kg and 3.5 hours, respectively. After a constant rate infusion, diltiazem was also shown to exhibit (45) nonlinear pharmacokinetics. After IV administration the following pharmacokinetic parameters were determined in healthy male volunteers the elimination t-1/2 (40) was 11.2 hours and the total clearance was 11.5 mL/min/kg. Diltiazem elimination is affected by liver damage (46) but not by kidney failure. 

Pharmacokinetic analysis showed that elimination of diltiazem in the elderly is disturbed, with a prolongation of the t-1/2 and an increase in the AUC as compared to control subjects (47). 

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