Lack of indinavir effects on methadone disposition despite inhibition of hepatic and intestinal cytochrome P4503A (CYP3A)

Abstract

Background: Methadone disposition and pharmacodynamics are highly susceptible to interactions with antiretroviral drugs. Methadone clearance and drug interactions have been attributed to cytochrome P4503A4 (CYP3A4), but actual mechanisms are unknown. Drug interactions can be clinically and mechanistically informative. This investigation assessed effects of the protease inhibitor indinavir on methadone pharmacokinetics and pharmacodynamics, hepatic and intestinal CYP3A4/5 activity (using alfentanil), and intestinal transporter activity (using fexofenadine).

Methods: Twelve healthy volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone. This was repeated after 2 weeks of indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by miosis.

Results: Indinavir significantly inhibited hepatic and first-pass CYP3A activity. Intravenous alfentanil systemic clearance and hepatic extraction were reduced to 40-50% of control, apparent oral clearance to 30% of control, and intestinal extraction decreased by half, indicating 50% and 70% inhibition of hepatic and first-pass CYP3A activity. Indinavir increased fexofenadine area under the plasma concentration-time curve 3-fold, suggesting significant P-glycoprotein inhibition. Indinavir had no significant effects on methadone plasma concentrations, methadone N-demethylation, systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Methadone plasma concentration-effect relationships were unaffected by indinavir.

Conclusions: Despite significant inhibition of hepatic and intestinal CYP3A activity, indinavir had no effect on methadone N-demethylation and clearance, suggesting little or no role for CYP3A in clinical disposition of single-dose methadone. Inhibition of gastrointestinal transporter activity had no influence of methadone bioavailability.

Figure 1

Indinavir effects on first-pass and hepatic cytochrome P4503A (CYP3A) activity, assessed using alfentanil as a CYP3A probe. Pupil diameter change from baseline (miosis) was used as a surrogate for alfentanil plasma concentrations. Shown is miosis after (A) 43 μg/kg oral alfentanil and (B) 15 μg/kg intravenous alfentanil. Each data point is the mean ± SD (n=12).

Figure 2

Indinavir effects on first-pass and hepatic cytochrome P4503A (CYP3A) activity, assessed using alfentanil as a CYP3A probe. Shown are alfentanil concentrations after (A) oral (43 μg/kg) and (B) intravenous (15 μg/kg) administration. Subjects received their morning indinavir dose 3 hr after intravenous alfentanil and 2 hr after oral alfentanil administration. Each data point is the mean ± SD (n=12).

Figure 3

Indinavir effects on gastrointestinal transporter activity, assessed using fexofenadine as a transporter probe. Each subject received 60 mg oral fexofenadine on all occasions. Each data point is the mean ± SD (n=12).

Figure 4

Effect of indinavir on intravenous methadone disposition. Shown are plasma (A) R-methadone, (B) R-EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine), (C) S-methadone and (D) S-EDDP concentrations. Subjects received 6.0 mg intravenous methadone HCl (5.4 mg free base). Each data point is the mean ± SD (n=12). Some SD are omitted for clarity.

Figure 5

Effect of indinavir on oral methadone disposition. Shown are plasma (A) R-methadone, (B) R-EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine), (C) S-methadone and (D) S-EDDP concentrations. Subjects received 11.0 mg oral methadone HCl (9.9 mg free base). Each data point is the mean ± SD (n=12). Some SD are omitted for clarity.

Figure 6

Effect of indinavir on stereoselective methadone elimination. The plasma R/S-methadone concentration ratios for (a) intravenous and (b) oral methadone are shown. Each data point is the mean ± SD (n = 12).

Figure 7

Relationship between methadone enantiomers clearance (CL) and cytochrome P4503A (CYP3A) activity. (A) Intravenous (IV) methadone clearance and hepatic CYP3A activity (IV alfentanil CL). Spearman correlation coefficients were 0.36 and 0.35 for R- and S-methadone, respectively, both p>0.05. (B) Apparent oral methadone CL and first-pass CYP3A activity (oral alfentanil apparent CL). Spearman correlation coefficients were 0.40 and 0.20 for R- and S-methadone, respectively, both p>0.05. Each data point is the result for a single subject. There were no significant correlations between methadone clearance and CYP3A activity.

Figure 8

Effect of indinavir on methadone pharmacodynamics. Subjects simultaneously received 11.0 mg oral and 6.0 mg intravenous methadone HCl. Each data point is the mean ± SD (n=12). Some SD are omitted for clarity. (A) Total (intravenous d0 and oral d5) plasma R-methadone concentrations. (B) Dark-adapted pupil diameter change from baseline (miosis). (C) Plasma concentration-effect relationships (miosis vs total R-methadone plasma concentration). Each data point is the mean concentration and mean effect at each time point.