Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2

BACKGROUND AND PURPOSE

Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.

EXPERIMENTAL APPROACH

Itraconazole (20 mg·kg⁻¹) and metformin (100 mg·kg⁻¹) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V_max), Michaelis–Menten constant (K_m) and intrinsic clearance (CL_int) for the disappearance of each drug, apparent inhibition constant (K_i) and [I]/K_i ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro.

KEY RESULTS

After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration–time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes.

CONCLUSIONS AND IMPLICATIONS

The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.     

P-glycoprotein expression in plasma-cell myeloma is associated with resistance to VAD

Tumor cell-associated expression of multidrug resistance (MDR) was quantitated in 22 patients with DNA-aneuploid myeloma using 2-parameter flow cytometry with monoclonal antibody (MoAb) C-219 for the detection of cytoplasmic p-170 and propidium iodide for nuclear DNA content. The proportion of cells expressing p-170 and the intensity of p-170-related fluorescence were determined for each patient. Among the 14 patients treated with vincristine-adriamycin-dexamethasone (VAD), the proportion of p-170-positive cells distinguished sensitive from resistant disease (P less than .01). Among a subgroup of seven patients with MDR analysis available prior to VAD therapy, two subsequent nonresponders had high proportions of C-219-reactive cells. The presence de novo of high proportions of p-170-expressing cells in another still untreated patient and in a further individual with resistance to dexamethasone and interferon (not associated with MDR) warrants systematic analysis of p-170 expression prior to therapy to determine its clinical implications for response to MDR-associated drugs as combined in the VAD regimen. Concurrent MDR expression by aneuploid tumor cells and cells in the diploid subcompartment may represent involvement of diploid cells in the myeloma disease process.     

Red blood cell indices and iron status according to feeding practices in infants and young children

With the electronic counters routinely used, it has become practical to determine the concentration of hemoglobin, red cell indices, and RDW concurrently in association with transferrin saturation and ferritin in accordance with feeding practices. The 1028 infants and children aged 6 to 24 months, who had been mainly admitted with acute infectious or inflammatory diseases, were divided into three groups, i.e., children who were exclusively breast-fed more than 6 months (group A), those who had been given iron-fortified formula milk since birth (group B), and those who had been given breast milk for 5–6 months and then switched to the iron-fortified formula (group C). Children with anemia comprised 34.8% (104/299) of group A, significantly more than 5.6% (34/608) of group B and 6.6% (8,/121) of group C ( p < 0.001, respectively). Children with MCV < 70 fl comprised 39.5% (118/299) of group A, significantly more than 7.1% (43/608) of group B and 13.2% (16/121) of group C. Out of the total 146 patients with anemia, 82.2% ( n = 120) had laboratory evidence of iron deficiency, which was mostly suggested by a dietery history. The sensitivity of MCV values < 70 fl in IDA patients was 90.0%; specificity was 53.8%. The sensitivity of RDW values ≥ 15% was 83.3%; specificity was 57.7%. The positive predictive value could be increased to 97.8% by combining MCV < 70 fl and RDW ≥ 15%. The sensitivity of serum ferritin concentrations < 10ng/ml was 62.4% and specificity was 100%. The sensitivity of transferrin saturation < 12% was 72.3% and specificity was 81.3%. By combining the hemoglobin with MCV and RDW in screening for iron deficiency, the diagnostic accuracy of IDA can be increased. We support the use of appropriately iron-fortified weaning foods or the routine iron supplement starting at 6 months of age in exclusively breast-fed infants.     

Postseptal cellulitis: CT in diagnosis and management

Thirteen orbital computed tomographic (CT) scans were obtained in 12 patients with postseptal (orbital) cellulitis. Sinus radiographs, which were also obtained, were not helpful in diagnosis or management. The location and extent of the inflammatory process was accurately demonstrated with axial CT scans in all cases. A protocol using CT in the management of postseptal cellulitis is proposed.     

Maternal behaviors: evidence that they feed back to alter brain morphology and function

We review evidence suggesting that the brain of maternally behaving rats is altered as a result of the behavior of the animal towards her pups. Morphological changes seen in the supraoptic nucleus, which contains oxytocinergic neurons important for lactation, are observed not only in parturient, lactating animals but also in virgin animals induced by the presence of rat pups to behave maternally. The supraoptic nuclei of lactating and maternally behaving virgin animals have a higher incidence of dendritic bundling relative to non-maternal virgin animals. Also, stimulation of the lateral olfactory tract in in vitro brain slices elevates electrotonic coupling among supraoptic neurons only in maternally behaving animals and not in male or non-maternal virgins. In general the evidence presented supports the idea that maternal behavior in lactating and non-lactating animals, can have profound effects on the morphology and physiological functioning of oxytocinergic neurons in the hypothalamus.