Abstract
To quantitatively evaluate drug-drug interactions involving metabolic processes in the liver, we attempted to predict the increasing ratio of the plasma concentration of midazolam (MDZ) in the presence of cimetidine (CIM) or nizatidine (NZD) in rats. Under steady-state conditions for the plasma concentration of CIM or NZD, MDZ was administered through the portal vein. The AUC of MDZ in the presence of CIM was 2.5-fold higher than that in the absence of CIM. There was no effect of NZD on the AUC of MDZ. The liver/plasma concentration ratios for CIM and NZD were 4.0 and 2.7, respectively. The estimated liver unbound concentration (CH,f )/plasma unbound concentration (Cp,f ) ratios for CIM and NZD were 1.9 and 2.4, respectively, suggesting concentrative hepatic accumulation of both drugs. The oxidative metabolism of MDZ in rat liver microsomes was competitively inhibited by CIM or NZD, and theKi values of CIM and NZD were 110 and 2600 μM, respectively. Based on these data obtained in vivo and in vitro, the increasing ratios for MDZ in the presence of CIM or NZD were predicted using the equationsRp = 1 +Cp,f /Ki andRH = 1 +CH,f /Ki . The observed increasing ratios in the presence of CIM were very close to RH , compared withRp . However,Cp,f andCH,f were much less thanKi and there was no difference betweenRp and RH in the presence of NZD. Consequently,Cp,f andCH,f were greater than or equal toKi and Cp,f was not equal to CH,f , as in the presence of CIM, and it was indicated that CH,f was more suitable for quantitatively predicting the drug-drug interactions than was Cp,f .
Footnotes
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Send reprint requests to: Yasufumi Sawada, Faculty of Pharmaceutical Sciences, Kyushu University, 3–1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
- Abbreviations used are::
- CYP
- cytochrome P450
- CIM
- cimetidine
- NZD
- nizatidine
- RAN
- ranitidine
- FAM
- famotidine
- MDZ
- midazolam
- Kp,H
- liver/plasma concentration ratio
- fH
- liver unbound fraction
- Cp,f
- plasma unbound concentration
- CH,f
- liver unbound concentration
- fp
- plasma unbound fraction
- Received July 24, 1997.
- Accepted December 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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