1: Clin Pharmacokinet. 2007;46(3):261-70. Alfentanil-induced miosis as a surrogate measure of alfentanil pharmacokinetics in patients with mild and moderate liver cirrhosis. Baririan N, Van Obbergh L, Desager JP, Verbeeck RK, Wallemacq P, Starkel P, Horsmans Y. Clinical Pharmacology and Gastroenterology Unit, St Luc University Hospital (Université Catholique de Louvain), Brussels, Belgium. OBJECTIVES: (i) To evaluate the pupillary response to alfentanil as a surrogate measure of alfentanil pharmacokinetics in cirrhotic patients and to compare the data observed in cirrhotic patients with those found in healthy volunteers (historical control group); and (ii) to compare this test with other liver function tests in cirrhotic patients. METHODS: Six patients with mild cirrhosis (Child-Pugh grade A) and six patients with moderate cirrhosis (Child-Pugh grade B) were studied after a single 15 microg/kg bolus of alfentanil. Alfentanil plasma concentrations were measured by liquid chromatography-tandem mass spectrometry, and pupillary responses were measured with a Pupilscan II pupillometer. Alfentanil pharmacokinetics (plasma concentration, area under the plasma concentration-time curve from time zero to infinity [AUC(infinity(p))] and from time zero to 2 hours [AUC(2(p))], apparent volume of distribution at steady state, clearance and terminal elimination half-life [t((1/2)(p))]) and miosis pseudo-kinetic parameters [AUC(infinity)((miosis)), AUC(2)((miosis)), t((1/2))((miosis))] were determined using a noncompartmental analysis method. In six patients (three Child-Pugh grade A and three Child-Pugh grade B), antipyrine (measure of liver intrinsic activity) and D-sorbitol (measure of liver blood flow) tests were performed. RESULTS: A significant correlation was found between the alfentanil AUC(infinity(p)) and AUC(infinity)((miosis)) (r = 0.6, p < 0.05) in cirrhotic patients. This correlation was even more significant if AUC determinations were limited to the first 2 hours after alfentanil administration (r = 0.9, p < 0.01). Statistically significant differences in pharmacokinetics and miosis pseudo-kinetic parameters were observed between cirrhotic patients and healthy volunteers from our previous experiment (historical control group). The correlations were significant between alfentanil clearance and antipyrine clearance (n = 6, r = 0.9, p < 0.05), alfentanil clearance and steady-state hepatic blood clearance [CL(H(b))] measured by the D-sorbitol test (n = 6, r = 0.9, p < 0.05). CONCLUSION: Alfentanil pharmacokinetic parameters were correlated with miosis pseudo-kinetic parameters in cirrhotic patients. There was a significant decrease in pharmacokinetics and miosis pseudo-kinetics in cirrhotic patients compared with volunteers from the historical control group. Alfentanil-induced miosis has the advantage of being noninvasive and can be limited to miosis measurements during the first 2 hours after alfentanil administration in cirrhotic patients. We thus propose to substitute the AUC(2(miosis)) for alfentanil pharmacokinetics in cirrhosis. PMID: 17328584 [PubMed - indexed for MEDLINE] Related Links A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. [Clin Pharmacol Ther. 2001] PMID:11753266 Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity. [Clin Pharmacol Ther. 2003] PMID:12621385 Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis. [Clin Pharmacol Ther. 2004] PMID:15536460 Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimally invasive and noninvasive probes for hepatic and first-pass CYP3A activity. [J Clin Pharmacol. 2005] PMID:16172184 Alfentanil-induced miosis clearance as a liver CYP3A4 and 3A5 activity measure in healthy volunteers: improvement of experimental conditions. [J Clin Pharmacol. 2005] PMID:16291719