Nifedipine AUC

Grapefruit juice Coadministration of nifedipine and grapefruit juice resulted in an approximately twofold increase in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations are most likely due to the inhibition of CYP3A4-related first-pass metabolism. Coadministration of nifedipine and grapefruit juice is to be avoided. 

In a randomised, placebo-controlled study, 9 healthy subjects were given a single 10-mg nifedipine capsule after a 5-day course of nafcillin 500 mg four times daily. The nifedipine AUC was decreased by 63% and the clearance was increased by 145%, but the effect of these changes on nifedipine pharmacodynamics was not assessed. It was suggested that nafcillin is an inducer of cytochrome P450 isoenzymes, and increased the metabolism of nifedipine. The clinical significance of these changes is unclear. 

After taking phenobarbital 100 mg daily for 2 weeks the clearance of a single 20-mg dose of nifedipine in a cocktail also containing sparteine, mephenytoin and antipyrine was increased almost threefold in 15 healthy subjects. The nifedipine AUC was reduced by about 60%. ... 

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. 

Concomitant treatment with the CYP3A4 substrate nifedipine altered the mean AUC and mean Cmax of repaglinide by 11 and 3% respectively (64). 

Oral rifampin dose and AUC changes abstracted from alfentanil (205), buspirone (208), gefitinib (209), L-a-acetylmethadol (210), midazolam (77) nifedipine (62), simvastatin (211), tamoxifen (212), toremifene (212), triazolam (213), and verapamil (60). 

CALCIUM CHANNEL BLOCKERS BUSULFAN t plasma concentrations of busulfan and t risk of toxicity of busulfan such as veno-ocdusive disease and pulmonary fibrosis, when co-administered with diltiazem, nifedipine or verapamil Due to inhibition of CYP3A4-mediated metabolism of busulfan by these calcium channel blockers. Busulfan clearance may be l by 25%, and the AUC of busulfan may t by 1500 p,mol/L Monitor clinically for veno-ocdusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUC of below 1500 p,mol/L per minute tends to prevent toxicity... 

The histamine H2 receptor antagonist cimetidine increases plasma concentrations of nifedipine and delays its elimination by inhibition of hepatic mono-oxygenases. Maximum plasma nifedipine concentrations and AUC can be increased by as much as 80%, and this results in a significant increase in the antihypertensive and antian-ginal effects of nifedipine and also toxicity (191,192). 

Vincristine Nifedipine Increase in AUC (3.4-fold) P-gp, CYP3A4 Fedeli et al. (1989)... 

Fig. 1. Frequency distribution of the area under the plasma concentration versus time curve (AUC) of nifedipine in plasma after oral administration of 20 mg nifedipine to 130 healthy subjects (from [5]). There is 10-fold interindividual variability in AUC in this...

To assess in a single session the incidence of the poor-metabolizer phenotypes for sparteine and mephenytoin, and the variability in nifedipine metabolism, in a Dutch population of 172 subjects [20]. A 7.4% incidence of poor metabolizers of sparteine was detected, which is quite similar to that found in other Caucasian populations. For mephenytoin 2.3% of this population was found to poorly metabolize it to para-hydroxymephenytoin. In a similar study in 130 healthy subjects a cocktail of phenytoin, sparteine and nifedipine was administered [22], The results of this study for nifedipine have been presented in Fig. 1, whereas a similar extent of variability in the plasma kinetic (AUC) for phenytoin was observed. Correlations between relevant kinetic and metabolic parameters of the three probe drags were all low and non-significant. None of the data of nifedipine and phenytoin were different between extensive and poor metabolizers of sparteine. Thus the major oxidative metabolic pathways of nifedipine, sparteine and phenytoin are not related to each other. The three compounds can in principle be used... 

A similar correlation approach (but not as a cocktail ) was used to elucidate similar rate-limiting steps in the metabolism of dihydropyridine calcium channel blockers. Racemic felodipine, racemic nitrendipine and nifedipine were investigated in a randomized cross-over study in healthy subjects, using stereoselective enantiomers. The high correlations between the AUCs of all compounds strongly suggest the involvement of the same or very similar enzyme(s) in their primary oxidative metabolism, which in all cases involves aromatization of the dihydropyridine ring stmcture [22]. 

Blood pressure may fall sharply when calcium-channel blockers are first given to patients already taking alpha blockers (particularly prazosin and terazosin), and vice versa. In a small study, tamsulosin did not have any clinically relevant effects on blood pressure well controlled by nifedipine. Verapamil may increase the AUC of prazosin and terazosin. Alpha blockers and calcium-channel blockers may be combined for additional blood pressure lowering in patients with hypertension. 

A further study in 12 healthy subjects found that the AUC of a single 200-mg oral dose of quinidine sulphate was increased by 16% by nifedipine 20 mg. The quinidine clearance was reduced by 14% and the maximum serum level was raised by almost 20%. These modest changes were not considered clinically relevant. ... 

In 8 healthy subjects the AUC and peak serum levels of a single 200-mg dose of cefixime were increased by about 70% and 50%, respectively, when cefixime was taken 30 minutes after a 20-mg dose of nifedipine. The rate of absorption was also increased. One suggested reason for this interaction is that the nifedipine increases the absorption of the cefixime by affecting the carrier system across the epithelial wall of the gut. It seems doubtful if this increased cefixime bioavailability is clinically important (the combination was well-tolerated) and no particular precautions would seem to be necessary on concurrent use. 

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