Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-21
2003-01-21
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06509371
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method of increasing the oral bioavailability of compounds by coadministration of the compound with Bergamottin (BG) to a patient. More particularly, the present invention concerns the use of BG to inhibit the intestinal enzymatic metabolism of compounds having low bioavailability. Specifically, inhibition of intestinal cytochrome P450 3A4 by BG decreases the intestinal metabolism of the compounds and increases their oral bioavailability. Additionally, the present invention relates to pharmaceutical compositions which include BG in combination with a compound having low bioavailability and a pharmaceutically acceptable carrier. Finally, the present invention relates to a method of isolating BG from grapefruit juice.
Oral bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by the oral route. Bioavailability generally can be defined as the fraction of unchanged drug reaching the systemic circulation following administration to a patient through any treatment route. Enhancing bioavailability of pharmaceutical agents has drawn a lot of attention for drug development and clinical pharmacology. Since P450 1A4 is the major P450 enzyme expressed in the intestines and is involved in the metabolism of a broad spectrum of clinically used drugs, it is considered to be one of the major determinant for oral bioavailability of these drugs. Some costly drugs, such as cyclosporine, FK506, taxol, indinavir, saquinavir and etc., are found to be metabolized extensively by P450 3A4. Coadministration of some of these drugs with P450 3A4 inhibitors have been found to increase their bioavailability.
Oral coadministration of grapefruit juice has been demonstrated to significantly increase the oral bioavailability of several clinically used drugs including dihydropyridines (Bailey D. G., Spence J. D., Munoz C., and Arnold J. M. O. Interaction of citrus juices with felodipine and nifedipine.
Lancett,
1991;337:268-269 and Bailey D. G., Arnold J. M. O., Bend J. R., Tran L. T., and Spence J. D. Grapefruit juice—felodipine interaction: reproducibility and characterization with the extended release drug formulation.
Br. J. Clin. Pharmacol,
1995;40:135-140), cyclosporine A (Ducharme M. P., Warbasse L. H., characterization with the extended release drug formulation
Br. J. Clin. Pharmacol,
1995;40:135-140), cyclosporine A (Ducharme M. P., Warbasse L. H., and Edwards D. J. Disposition of intravenous and oral cyclosporine after administration with grapefruit juice.
Clin. Pharmacol. Ther.,
1995;57:485-491), midazolam (Kuferschmidt H. H., Ha H. R., Ziegler W. H., Meier P. J., and Krahenbuhl S. Interaction between grapefruit juice and midazolam in humans,
Clin. Pharmacol. Ther.,
1995;58:20-28), triazolam (Hukkinen S. K., Varhe A., Olkkola K. T., and Neuvonen P. J. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice.
Clin. Pharmacol. Ther.,
1995;58:127-131), terfenadine (Benton R. E., Hoig P. K., Zamaani K., Cantilena L. R., and Woosley R. L. Grapeffuit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram.
Clin. Pharmacol. Ther.,
1996;59:383-388), and ethinyl estradiol (Weber A., Jager R., Borner A., Klinger G., Vollanth R., Mathey K., and Balogh A. Can grapefruit juice influence ethinylestradiol bioavailability?
Contraception,
1996;53:41-47). Since all of these drugs are metabolized primarily by cytochrome P450 3A4, the predominant intestinal and hepatic P450 enzyme (Shimada T., Yamazaki H., Mimura M., Inui Y., and Guengerich F. P. Interindividual variation in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians.
J. Pharmacol. Exp. Ther.,
1994;270:414-422 and Watkins P. B., Wrighton S. A., Schuetz E. G., Molowa D. T., and Guzelian P. S. Identification of glucocorticoid—inducible cytochrome P-450 in the intestinal mucosa of rats and man.
J. Clin. Invest.,
1987;80:1029-1036), suggested that the grapefruit juice effect may be due to the inhibition of P450 3A4 activity. More recently, grapefruit juice has been shown to dramatically decrease the immunoreactive P450 3A4 content in enterocytes of human intestines with no change in the content of P450 3A4 mRNA (Lown K. S., Bailey D. G., Fontana R. J., Janardan S. K., Adair C. H., Fortlage L. A., Brown M. B., Guo W., and Watkins P. B. Grapefruit juice increases felodipine oral bioavailability in humans by decreasing intestinal CYP 3A protein expression.
J. Clin. Invest.,
1997;99:1-9). These results suggest that the degradation of P450 3A4 protein may be accelerated by ingestion of grapefruit juice (Lown, Supra, 1997). Because suicide inactivation of rat P450 3A could accelerate degradation of the apoP450 (Correia M. A., Davoll S. H., Wrighton S. A., and Thomas P. E. Degradation of rat liver cytochrome P450 3A after their inactivation by 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine: characterization of the proteolytic system.
Arch. Biochem. Biophys.,
1992;297:228-238), mechanism based-inactivation of P450 3A4 has been suggested to be involved in grapefruit juice effects.
In order to identify the principle components in grapefruit juice responsible for increasing the bioavailability of some drugs, flavonoids, such as naringenin, naringin, quercetin, and kaemferol, have been chosen as possible candidates because they have been shown to competitively inhibit P450 3A4 activity in vitro (Miniscalco A., Lundahl J., Regardh C. G., Edgar B., and Eriksson U. G. Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice.
J. Pharmacol. Exp. Ther.,
1992;261;1195-1199 and Ghosal A., Satoh H., Thomas P. E., Bush E., and Moore D. Inhibition and kinetics of cytochrome P450 3A4 activity in microsomes from rat, human and cDNA-expressed human cytochrome P450.
Drug Metab. Dispos.,
1996;24:940-947). However, oral administration of these flavonoids did not produce the grapefruit juice effects (Bailey D. G., Arnold J. M. O., Munoz C., and Spence J. Grapefruit juice—felodipine interaction: mechanism, predictability, and effect of naringin.
Clin. Pharmacol. Ther.,
1993;53;637-642 and Rashid J., McKinstry C., Renwick A. G., Dirnhuber M., Waller D. G., and George C. F. Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice.
Br. J. Clin. Pharmac.,
1993;36:460-463). Recently, HPLC purification of methylene chloride extract of grapefruit juice led to the identification of 6′,7′-dihydroxybergamottin as a component of grapefruit juice which caused inhibition of testosterone 6&bgr;-hydroxylase in liver microsomes from dexamethasone-induced rats (Edwards D. J., Bellevue F. H., III, and Woster P. M. Identification of 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice.
Drug Metab. Dispos.,
1996;24:1287-1290).
We have surprisingly and unexpectedly found that BG is the primary compound in grapefruit juice responsible for the mechanism-based inhibition of human cytochrome P450 3A4. Thus, coadministration of a compound having low oral bioavailability in combination with BG can be used to increase the oral bioavailability of the compound.
SUMMARY OF THE INVENTION
Accordingly, a first embodiment of the present invention provides a method of inhibiting enzymatic intestinal metabolism of a compound having low bioavailability comprising administering the compound in combination with BG to a patient.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound having low bioavailability in combination with BG in unit dosage form.
Finally, the present invention is directed to a method of isolating BG from grapefruit juice.
REFERENCES:
patent: 5665386 (1997-09-01), Benet et al.
patent: 571
He Kan
Hollenberg Paul F.
Woolf Thomas F.
Fay Zohreh
Kwon Brian-Yong S.
Merchant & Gould P.C.
Warner-Lambert & Company
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