Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Nov 2004
Randomized Controlled Trial Comparative Study Clinical TrialIntravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis.
Systemic clearance of intravenous (IV) alfentanil (ALF) is an in vivo probe for hepatic cytochrome P450 (CYP) 3A activity, miosis is a surrogate for plasma ALF concentrations, and IV ALF miosis is a noninvasive probe for hepatic CYP3A. This investigation characterized the bioavailability and first-pass metabolism of oral ALF and tested the hypotheses that (1) first-pass ALF clearance reflects first-pass CYP3A activity, (2) miosis after oral ALF will reflect intestinal and hepatic CYP3A activity, and (3) miosis can approximate plasma concentration-based pharmacokinetic measures for IV and oral ALF as a noninvasive in vivo probe for hepatic and first-pass CYP3A activity and drug interactions. Results were compared with those for midazolam (MDZ), an alternative CYP3A probe. ⋯ ALF and MDZ have similar intestinal extraction but low and intermediate hepatic extraction, respectively. Systemic and oral clearances of ALF are excellent in vivo probes for hepatic and first-pass CYP3A activities and drug interactions. Miosis was an acceptable surrogate for plasma ALF. ALF miosis may be a suitable noninvasive in vivo probe for both hepatic and first-pass CYP3A.
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Clin. Pharmacol. Ther. · Oct 2004
Randomized Controlled Trial Clinical TrialAngiotensin-converting enzyme inhibition and smoking potentiate the kinin response to cardiopulmonary bypass.
This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors potentiate activation of the kallikrein-kinin system during cardiopulmonary bypass (CPB). ⋯ Preoperative ACE inhibitors and smoking potentiate the kinin response to CPB and may contribute to the hemodynamic and fibrinolytic response observed during CPB.
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Clin. Pharmacol. Ther. · Oct 2004
Randomized Controlled Trial Clinical TrialDifferent dosage regimens of rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotype status.
For the treatment of gastroesophageal reflux disease, intragastric pH should be lower than 4.0 for no more than 4 hours a day (<16.7%). We aimed to develop optimal dosage regimens for rabeprazole to control nocturnal acidity in relation to cytochrome P450 (CYP) 2C19 genotypes. ⋯ We propose that rabeprazole dosage regimens for sufficient acid inhibition are 20 mg once daily for PMs, 20 mg twice daily for heterozygous EMs, and 10 mg 4 times daily for homozygous EMs or heterozygous EMs.
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Clin. Pharmacol. Ther. · Sep 2004
Randomized Controlled Trial Clinical TrialRole of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone.
The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans. ⋯ First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.
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Clin. Pharmacol. Ther. · Jun 2004
Randomized Controlled Trial Comparative Study Clinical Trial6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect.
Our objective was to assess the contribution of 6',7'-dihydroxybergamottin (DHB) to the inhibitory effect of grapefruit juice toward intestinal cytochrome P450 (CYP) 3A4. ⋯ The interaction between grapefruit juice serum and felodipine can be attributed largely to DHB. This establishes DHB as an important contributor to the grapefruit juice effect.