Biomaterial Database

Integrated pharmacokinetic and metabolic modeling of ipriflavone and metabolites after oral administration. 1997

S Rohatagi, and J S Barrett

DuPont Merck Pharmaceuticals, Stine-Haskell Research Center, Newark, DE 19714, USA.

OBJECTIVE Disposition of ipriflavone, an agent indicated for the treatment of osteoporosis, is highly variable after oral administration. Ipriflavone has five major metabolites (M1, M2, M3, M4, and M5). The metabolites M2 and M5 have activity and are major metabolic constituents in humans. Hence, it is important to characterize both ipriflavone and metabolites simultaneously. Our purpose was to develop an integrated pharmacokinetic/metabolic model that simultaneously predicts plasma concentrations of ipriflavone and metabolites after a single oral administration. METHODS The model was based on the reported metabolic conversion of ipriflavone to M1, M3, and M4; subsequent conversion of M4 to M5; and conversion of both M1 and M3 to M2 in rats. The further conversion of M5 to M6 and M7 was ignored, as this conversion represents an insignificant portion of the total metabolite pool. The input function was described by a first-order constant. Each analyte required two-compartment disposition. The elimination/nonmetabolic constants for each analyte accounted for urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which 16 healthy male volunteers were administered 200 mg of an ipriflavone corn suspension were used to examine the predictability of this model. RESULTS The coefficient of determination was 0.99, and model selection criterion was 3.7 for mean data fits supporting the goodness-of-fit and predictability of the model. The model also predicted negligible urinary recoveries for ipriflavone, M1, M3, and M4; M2 and M5 had high urinary recoveries. The metabolic conversion constant from M3 to M2 was negligible. Divergence from the proposed pathway may be attributed to the species differences in metabolism between humans and rats. CONCLUSIONS Model predictions supported the improvement in bioavailability with corn-oil suspension compared to the conventional oral tablet. Future model applications may also help identify significant covariates (i.e., age, gender, and disease state) in proposed clinical trials.

UI	MeSH Term	Description	Entries
D007529	Isoflavones	3-Phenylchromones. Isomeric form of FLAVONOIDS in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position.	3-Benzylchroman-4-One,3-Benzylidene-4-Chromanone,Homoisoflavone,Homoisoflavones,Isoflavone,Isoflavone Derivative,3-Benzylchroman-4-Ones,3-Benzylidene-4-Chromanones,Isoflavone Derivatives,3 Benzylchroman 4 One,3 Benzylchroman 4 Ones,3 Benzylidene 4 Chromanone,3 Benzylidene 4 Chromanones,Derivative, Isoflavone,Derivatives, Isoflavone
D008297	Male		Males
D008954	Models, Biological	Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.	Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D003314	Corn Oil	Oil from ZEA MAYS or corn plant.	Maize Oil,Lipomul,Corn Oils,Lipomuls,Maize Oils,Oil, Corn,Oil, Maize,Oils, Corn,Oils, Maize
D006207	Half-Life	The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.	Halflife,Half Life,Half-Lifes,Halflifes
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284	Administration, Oral	The giving of drugs, chemicals, or other substances by mouth.	Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D000328	Adult	A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available.	Adults
D000465	Algorithms	A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task.	Algorithm
D001711	Biotransformation	The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.