Clinical pharmacokinetics of nifedipine gastrointestinal therapeutic system

Chung, Mun Su; Reitberg, Donald P.; Gaffney, Michael; Singleton, W. S.

doi:10.1016/0002-9343(87)90630-9

Cited by 124 publications

(66 citation statements)

References 8 publications

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“…The antihypertensive nifedipine as well as the antiarrythmic amiodarone are CYP3A substrates and maintenance therapies commonly paired in this patient population. Due to these agents' narrow therapeutic window, both are subject to clinical DDIs through the induction of CYP3A4 (Latini et al, 1984;Chung et al, 1987). Rodent and human hepatocytes were incubated with either a pan-P450 inhibitor (miconazole), our structurally unrelated CYP3A activator VU0448187, or flutamide and its metabolite 2-OH-Flu in a full concentration-response experiment with the commonly paired CYP3A substrates nifedipine and amiodarone.…”

Section: Resultsmentioning

confidence: 99%

“…Drugs such as nifedipine (antihypertensive) and amiodarone (antiarrythmic) are subject to DDI scenarios in patients when coadministered with potent CYP3A4 inducers due to reductions in plasma exposures of the parent drug (nifedipine) (Chung et al, 1987) or increases in the formation of pharmacologically active and hepatotoxic metabolites (amiodarone) (Latini et al, 1984). Both drugs are often prescribed to prostate cancer patients receiving a polypharmacy approach to treatment (Fabre et al, 1993;Patki et al, 2003) and are metabolized primarily by CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

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A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo

et al. 2015

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Once thought to be an artifact of microsomal systems, atypical kinetics with cytochrome P450 (CYP) enzymes have been extensively investigated in vitro and found to be substrate and species dependent. Building upon increasing reports of heterotropic CYP activation and inhibition in clinical settings, we screened a compound library of clinically approved drugs and various probe compounds to identify the frequency of heterotropism observed with different drug classes and the associated CYP enzymes thereof (1A2, 2C9, 2D6, and 3A4/5). Results of this screen revealed that the prescribed androgen receptor antagonist flutamide activated the intrinsic midazolam hydroxylase activity of CYP3A in human hepatic microsomes (66%), rat and human hepatocytes (36 and 160%, respectively), and in vivo in male Sprague-Dawley rats (>2-fold, combined area under the curve of primary rat in vivo midazolam metabolites). In addition, a screen of the pharmacologically active metabolite 2-hydroxy-flutamide revealed that this principle metabolite increased CYP3A metabolism of midazolam in human microsomes (30%) and hepatocytes (110%). Importantly, both flutamide and 2-hydroxy-flutamide demonstrated a pronounced increase in the CYP3A-mediated metabolism of commonly paired medications, nifedipine (antihypertensive) and amiodarone (antiarrhythmic), in multispecies hepatocytes (100% over baseline). These data serve to highlight the importance of an appropriate substrate and in vitro system selection in the pharmacokinetic modeling of atypical enzyme kinetics. In addition, the results of our investigation have illuminated a previously undiscovered class of heterotropic CYP3A activators and have demonstrated the importance of selecting commonly paired therapeutics in the in vitro and in vivo modeling of projected clinical outcomes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo

et al. 2015

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“…These were adjusted slightly to provide a better fit of some mean data collected in subjects after an oral dose of 10 mg nifedipine as a soft gelatin capsule (Fig. 6a) (31). The T ppt value was 90,000 s, i.e., precipitation did not occur.…”

Section: Resultsmentioning

confidence: 99%

“…Nifedipine was marketed as Procardia XL, as 60 mg 18 h modified release (MR) formulation "gastrointestinal therapeutic system" (GITS™) to reduce side effects and administration frequency (31). The formulation delivered a gel of nifedipine and excipients at a rate of about 3.3 mgA/h.…”

Section: Resultsmentioning

confidence: 99%

Role of Physiological Intestinal Water in Oral Absorption

Sutton

2009

AAPS J

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Abstract. Water volume has impact when the compound has low aqueous solubility. For example, the absorption of compounds with a Biopharmaceutics Classification System class 2 or 4 is likely to be solubility-limited. Provided the formulation does not contribute to a dissolution-limited condition (e.g., particle size, Waterman and Sutton, J Control Release 86: [293][294][295][296][297][298][299][300][301][302][303][304] 2003) and permeability is rapid, any impact on solubility factors in the gastrointestinal (GI) tract will directly impact the fraction absorbed These factors are in situ solubility, precipitation, and volume of water. Using GastroPlus™, models were developed with literature values of water volume in the small (SIWV) and large (LIWV) intestines for several solubility limited compounds. One or more models were developed for the mean plasma concentration-time profile of each compound. The consistency of the models with known literature and experimental data for the compounds' solubility and precipitation was determined. The SIWV associated with best fits of solubility limited compounds averaged about 130 ml, with a range of 10-150 ml in the fasted state. The average LIWV in the fasted state was about 10 ml and ranged as large as 125 ml. The wide range of individual LIWV values is likely due to variability in pharmacokinetics, permeability, GI transit, and the observation that data set was collected during a "snapshot in time". The preferred values of 10% organ volume for small intestine and 1-10% organ volume for large intestine are recommended in lieu of the GastroPlus default values of 40% and 10%, respectively.

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“…The plasma concentration of nifedipine can reach a plateau within 6 h and continue at that concentration for at least 24 h after administration. 28 The major advantage of our study is the measurement of steady-state plasma drug concentration on the sixteenth day. The fact that the positive findings remained after adjustment for plasma nifedipine concentration made our results much more convincing.…”

Section: Discussionmentioning

confidence: 99%

Arg347Cys polymorphism of α1A-adrenoceptor gene is associated with blood pressure response to nifedipine GITS in Chinese hypertensive patients

et al. 2009

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Our objectives were to evaluate whether polymorphisms in the a1A-and b2-adrenoceptor genes influence blood pressure response to nifedipine gastrointestinal therapeutic system (GITS). Hypertensive patients received daily treatment with an oral dosage of 30 mg nifedipine GITS for 16 days. Genotypes of the Arg347Cys polymorphism in the a1A-adrenoceptor gene and the Arg16Gly and Gln27Glu polymorphisms in the b2-adrenoceptor gene were determined by TaqMan single-nucleotide polymorphism genotyping assay. The sixteenth-day steady-state plasma concentration of nifedipine was measured using HPLC with UV detection. Multivariate linear regression was performed in a total of 447 patients to evaluate the effects of these polymorphisms on blood pressure response to nifedipine GITS. Patients carrying the Cys347 allele of the a1A-adrenoceptor gene had a greater systolic blood pressure reduction than did those carrying two Arg347 alleles of the a1A-adrenoceptor gene (32.5±14.0 versus 27.3±15.5 mm Hg, respectively, P¼0.006). However, diastolic blood pressure reduction was not associated with the Arg347Cys polymorphism in the a1A-adrenoceptor gene. In addition, no significant associations were observed between blood pressure reduction and two polymorphisms in the b2-adrenoceptor gene. Our data suggest that the Arg347Cys polymorphism in the a1A-adrenoceptor gene may be used to predict blood pressure response to nifedipine GITS in

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Clinical pharmacokinetics of nifedipine gastrointestinal therapeutic system

Cited by 124 publications

References 8 publications

A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo

A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo

Role of Physiological Intestinal Water in Oral Absorption

Arg347Cys polymorphism of α1A-adrenoceptor gene is associated with blood pressure response to nifedipine GITS in Chinese hypertensive patients

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