Effects of insulin on CYP3A activity and nicardipine disposition in streptozotocin-induced diabetic rats.
OBJECTIVE
The aim of the study was to clarify the effect of insulin treatment on drug metabolism and disposition.


METHODS
We investigated the mRNA expression and activity of cytochrome P450 (CYP) 3A, which is involved in the metabolism of several drugs, by using a rat model of diabetes and insulin-treated diabetes. In addition, we investigated the mRNA expression of the nuclear receptors reported to regulate the transcription of CYP3A, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). We also assessed the disposition of nicardipine, which is mainly metabolised by CYP3A, using both rat models to evaluate the influence of insulin treatment on drug disposition.


RESULTS
We noted that alterations in the serum bile acid concentration in both rat groups were related to the changes in CAR mRNA expression, CYP3A mRNA expression and CYP3A activity. Furthermore, although the enhanced CYP3A activity in the diabetic rat accelerated the elimination of nicardipine, insulin administration decreased the enhanced CYP3A activity in the diabetic group and delayed the elimination of nicardipine to the same level as that in the control group. However, the steady-state volume of distribution was increased in the insulin-treated diabetic group as compared to the control and diabetic groups. We further noted that although the CYP3A activity in the diabetic group returned to the same level as in that in the non-diabetic group by insulin treatment, other values, such as the distribution volume of nicardipine, did not show a similar return.


CONCLUSIONS
Based on our results, we suggest that alterations in the drug disposition in diabetes and insulin-treated diabetes should be taken into consideration in order to provide safe and effective drug therapy.
Hasegawa
Yoshitaka
Y
Laboratory of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
Kishimoto
Shuichi
S
Shibatani
Naoki
N
Inotsume
Nobuo
N
Takeuchi
Yoshikazu
Y
Fukushima
Shoji
S
D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D008658:Inactivation, Metabolic; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009529:Nicardipine / Q000493:pharmacokinetics*; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism
D001647:Bile Acids and Salts; D000090702:Constitutive Androstane Receptor; D007328:Insulin; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D009529:Nicardipine; D051544:Cytochrome P-450 CYP3A