Christine Hoffer

Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites

In vitro experiments suggest that circulating metabolites of oxycodone are opioid receptor agonists. Clinical and animal studies to date have failed to demonstrate a significant contribution of the O‐demethylated metabolite oxymorphone toward the clinical effects of the parent drug, but the role of other putative circulating active metabolites in oxycodone pharmacodynamics remains to be examined.

Role 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.

Role of P‐glycoprotein in the intestinal absorption and clinical effects of morphine

There is considerable and unexplained individual variability in the morphine dose‐effect relationship. The efflux pump P‐glycoprotein regulates brain access and intestinal absorption of numerous drugs. Morphine is a P‐glycoprotein substrate in vitro, and P‐glycoprotein affects morphine brain access and pharmacodynamics in animals. However, the role of P‐glycoprotein in human morphine disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous morphine are greater after inhibition of intestinal and brain P‐glycoprotein, with the P‐glycoprotein inhibitor quinidine used as an in vivo probe.

Intravenous 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.

Contribution of Itraconazole Metabolites to Inhibition of CYP3A4 in vivo

Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy‐itraconazole (OH‐ITZ), keto‐itraconazole (keto‐ITZ), and N‐desalkyl‐itraconazole (ND‐ITZ). The goal of this study was to determine the contribution of these metabolites to drug–drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH‐ITZ, keto‐ITZ, and ND‐ITZ were detected in plasma samples of all volunteers. A 3.9‐fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady‐state concentrations (Css,ave,u) and liver microsomal inhibition constants for ITZ, OH‐ITZ, keto‐ITZ, and ND‐ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam

The hepatic and first‐pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark‐adapted pupil diameters were determined coincident with blood sampling. In CYP3A5*3/*3 (n=62), *1/*3 (n=28), and *1/*1 (n=8) genotypes, systemic clearances of ALF were 4.6±1.8, 4.8±1.7, and 3.9±1.7 ml/kg/min and those of MDZ were 7.8±2.3, 7.7±2.3, and 6.0±1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8±7.2, 13.3±6.1, and 12.6±8.2 ml/kg/min for ALF and 35.2±19.0, 36.4±15.7, and 29.4±9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.

Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P‐Glycoprotein Activities

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short‐term (2‐day) and steady‐state (2‐week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P‐glycoprotein (P‐gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration‐time curve (AUC)0–∞/dose ratio (ritonavir/control) for oral ALF 25‐fold. Steady‐state ritonavir increased the AUC0–∞/dose ratio for IV and oral ALF 4‐ and 10‐fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first‐pass CYP3A >96%. Chronic ritonavir inhibits hepatic CYP3A (>70%) and first‐pass CYP3A (>90%). Acute and steady‐state ritonavir increased the fexofenadine AUC0–∞ 2.8‐ and 1.4‐fold, respectively, suggesting P‐gp inhibition. Steady‐state compared with acute ritonavir caused mild apparent induction of P‐gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.

Quinidine as a Probe for the Role of P-Glycoprotein in the Intestinal Absorption and Clinical Effects of Fentanyl

The mechanism of individual variability in the fentanyl dose‐effect relationship is unknown. The efflux pump P‐glycoprotein (P‐gp) regulates brain access and intestinal absorption of numerous drugs. Evidence exists that fentanyl is a P‐gp substrate in vitro, and P‐gp affects fentanyl analgesia in animals. However, the role of P‐gp in human fentanyl disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous fentanyl are greater after inhibition of intestinal and brain P‐gp, using the P‐gp inhibitor quinidine as an in vivo probe. Two randomized, double‐blind, placebo‐controlled, balanced, two‐period crossover studies were conducted in normal healthy volunteers (6 males and 6 females) after obtaining informed consent. Pupil diameters and/or plasma concentrations of fentanyl and norfentanyl were evaluated after oral or intravenous fentanyl (2.5 μg/kg), dosed 1 hour after oral quinidine (600 mg) or placebo. Quinidine did not alter the magnitude or time to maximum miosis, time‐specific pupil diameter, or subjective self‐assessments after intravenous fentanyl but did increase the area under the curve (AUC) of miosis versus time (13.6 ± 5.3 vs. 8.7 ± 5.0 mm•h, p < 0.05) and decreased the effect of elimination (kel 0.35 ± 0.16 vs. 0.52 ± 0.24 h−1, p < 0.05). Quinidine increased oral fentanyl plasma Cmax (0.55 ± 0.19 vs. 0.21 ± 0.1 ng/mL) and AUC (1.9 ± 0.5 vs. 0.7 ± 0.3 ng•h•mL−1) (both p < 0.05) but had no effect on apparent elimination. Plasma norfentanyl/fentanyl AUC ratios were not diminished by quinidine. Quinidine significantly increased maximum miosis after oral fentanyl (3.4 ± 1.3 vs. 2.3 ± 1.3 mm, p < 0.05), commensurate with increases in plasma concentrations, but concentration‐effect relationships and the rate constant for the transfer between plasma and effect compartment (ke0) (1.9 ± 1.0 vs. 3.6 ± 2.6 h−1) were not significantly different. Quinidine increased oral fentanyl plasma concentrations, suggesting that intestinal P‐gp or some other quinidine‐sensitive transporter affects the absorption, bioavailability, and hence clinical effects of oral fentanyl. Quinidine had less effect on fentanyl pharmacodynamics, suggesting that if quinidine is an effective inhibitor of brain P‐gp, then P‐gp appears to have less effect on brain access of fentanyl.

Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics I. Evidence against CYP3A mediation of methadone clearance

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus–negative volunteers. Subjects received intravenous plus oral (deuterium‐labeled) racemic methadone after no ritonavir, short‐term (3‐day) ritonavir, and steady‐state ritonavir. Acute and steady‐state ritonavir, respectively, caused 1.5‐ and 2‐fold induction of systemic and apparent oral R‐ and S‐methadone clearances. Ritonavir increased renal clearance 40–50%, and stereoselectively (S > R) increased hepatic methadone N‐demethylation 50–80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P‐glycoprotein. Intestinal and hepatic CYP3A was inhibited >70%. Ritonavir shifted methadone plasma concentration‐miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.

Disposition of nasal, intravenous, and oral methadone in healthy volunteers

Nasal administration of many opioids demonstrates rapid uptake and fast onset of action. Nasal administration may be an alternative to intravenous and oral administration of methadone and was therefore studied in human volunteers.