Planta Med 2008; 74 - PC145
DOI: 10.1055/s-0028-1084663

Furanocoumarins can affect oral bioavailability of drugs to both directions

M Vertzoni 1, V Kourafalos 2, I Kostakis 2, P Paterakis 3, D Rekkas 3, P Dallas 3, N Fokialakis 2, C Reppas 1
  • 1Laboratory of Biopharmaceutics and Pharmacokinetics, N&K University of Athens, Greece
  • 2Laboratory of Pharmacognosy and Chemistry of Natural Products, N&K University of Athens, Greece
  • 3Laboratory of Pharmaceutical Technology, N&K University of Athens, Greece

Objectives: Confirm that dog is an appropriate model for studying the effects of modulation of P450 enzymes on drug plasma levels, by administering nifedipine (CYP3A4 substrate) with and without a furanocoumarin rich material (FRM).

Study the effect of furanocoumarins on plasma levels of ketoconazole (CYP3A12 substrate). Furanocoumarins are both inhibitors and inducers of CYP3A12.

Methods: Grapefruits (Citrus medica, Rutaceae) were collected from Peloponnese (Greece). The pericarp was lyophilized and extracted with dichloromethane to obtain a semi-solid material (FRM) containing bergamotin derivatives (10.2%), a coumarin derivative (6.9%), and meranzine hydrate (3.1%). 10mg nifedipine were dissolved in 90mg Cremophor® EL and poured into a capsule (reference formulation) or they were mixed with 400mg FRM and transferred into the capsule (test formulation). 200mg ketoconazole were added into a capsule (reference formulation) or were suspended in 400mg of liquefied (after mild heating) FRM and then poured into the capsule (test formulation).

Four fasted dogs (24–31kg) were used. At separate occasions each dog was administered orally 500mL cow's milk with one reference formulation and with one test formulation. Plasma drug levels were monitored with HPLC.

Results: After administration of nifedipine reference formulation plasma levels were <3ng/ml (LOQ) whereas after administration of the test formulation Cmax and AUC0–12 were 15±7ng/ml and 50±41h×ng/ml, respectively. For ketoconazole, Cmax values were reduced after administration of the test formulation in all four dogs (1–33%).

Conclusions: As in humans, furanocoumarins increased nifedipine's bioavailability in dogs. Ketoconazole data suggest that fouranocoumarins can lead to reduction of Cmax values.