Barbara W. LeDuc

Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice

Components of grapefruit juice may impair the activity of intestinal cytochrome P450 (CYP) 3A enzymes, sometimes resulting in clinically important drug interactions. The time course of recovery from CYP3A inhibition after a single exposure to grapefruit juice is not clearly established.

Norcocaine and N-Hydroxynorcocaine Formation in Human Liver Microsomes: Role of Cytochrome P-450 3A4

Cocaine was metabolized to norcocaine by microsomes prepared from lymphoblastoid cells expressing transfected human P-450 3A4. The specific activities of norcocaine formation by microsomes prepared from three human liver samples correlated with the amount of P-450 3A immunoreactive protein detected by immunoblot. Triacetyloleandomycin, a specific inhibitor of P-450 3A isoforms, inhibited formation of norcocaine from cocaine, but not formation of N-hydroxynorcocaine from norcocaine. The chemical identity of the norcocaine and N-hydroxynorcocaine produced by human liver microsomes was established by combination of gas chromatography and mass spectrometry. Thus, human P-450 3A4 is a cocaine demethylase, and P-450 isoforms of the 3A family are responsible for the majority of norcocaine production by human hepatic microsomes.

Differential Effect of Cigarette Smoking on Antipyrine Oxidation versus Acetaminophen Conjugation

The effect of cigarette smoking on drug oxidation and conjugation was studied using antipyrine and acetaminophen as marker compounds. For the antipyrine study, healthy cigarette smokers (n = 30) and nonsmoking controls (n = 53) received a single 1.0-gram intravenous dose of antipyrine. For the acetaminophen study, 14 smokers and 15 nonsmokers received a 650-mg intravenous dose of acetaminophen. The clearance of antipyrine was significantly increased (0.93 vs. 0.60 ml/min/kg, p less than 0.0001) and elimination half-life was correspondingly reduced (8.9 vs. 13.0 h, p less than 0.0001) in smokers compared to nonsmoking controls. Total recovery of antipyrine and metabolites excreted in urine did not differ between groups, but there was a significantly increased fractional clearance of antipyrine via formation of 4-hydroxyantipyrine and 3-hydroxymethyl metabolites in smokers. Fractional clearance via formation of norantipyrine did not differ significantly between groups. Comparison of acetaminophen kinetics between smokers and nonsmokers indicated no significant differences in elimination half-life, clearance or volume of distribution. Thus, cigarette smoking is more likely to induce drug oxidation rather than drug conjugation. However, not all oxidative pathways are equally influenced; induction effects of smoking are highly substrate selective and pathway specific.

Large Theophylline Requirements due to High Theophylline Clearance: Verification by the Antipyrine Test

An asthmatic patient required very high doses of theophylline (2.88 g/day by intravenous infusion) to maintain an adequate serum theophylline concentration (12 micrograms/ml). His cigarette smoking and concurrent treatment with phenytoin were suspected to have produced hepatic microsomal enzyme induction, causing unusually high theophylline clearance. The intravenous antipyrine test demonstrated an unusually short half-life (5.5 h) and high clearance (95 ml/min) of antipyrine, consistent with induced clearance of antipyrine. Formation of the 4-hydroxy metabolite of antipyrine was disproportionately induced. Thus the antipyrine test can be of clinical value for documenting hepatic microsomal enzyme induction in patients with low steady-state theophylline concentrations despite high maintenance doses.

Poor bioavailability of CGS 8216 in a water/tween vehicle following intraperitoneal injection

Richard G. Lister 1, Barbara W. LeDuc 2, David J. Greenblatt 2, and Sandra E. File 3 1 Laboratory of Clinical Studies, NIAAA, Building I0 Room 3C218, 9000 Rockville Pike, Bethesda, MD 20892, USA 2 Division of Clinical Pharmacology, Tufts-New England Medical Center, 171 Harrison Avenue, Boston MA 02111, USA 3 MRC Neuropharmacology Unit, The School of Pharmacy, 29/39 Brunswick Square, London WC1N lAX, UK

Impaired absorption of tetracycline by colestipol is not reversed by orange juice

Nine volunteers received a 500 mg oral dose of tetracycline hydrochloride in three trials: A: With 180 ml water; B: With 30 gm colestipol in 180 ml water; C: With 30 gm colestipol in 180 ml orange juice. Tetracycline concentrations in multiple urine samples collected during 48 hours after each dose were determined by high pressure liquid chromatography. The three trials did not differ significantly in 48 hour cumulative urine volume (3086 vs 3207 vs 3194 ml for Trials A, B, and C). However, the three trials differed significantly in 48 hour excretion of tetracycline (F = 28.2; P < .001). During Trial A, mean excretion was 237 mg; this was significantly (P < .05) reduced to 109 mg in Trial B and 104 mg in Trial C. However, Trials B and C were not different. Thus, coadministration of tetracycline with colestipol significantly impairs tetracycline absorption by more than 50%. Mixing colestipol with orange juice does not alter colestipol‐induced impairment of tetracycline absorption.

Effect of antipyrine coadministration on the kinetics of acetaminophen and lidocaine.

SummaryPharmacokinetic interactions between antipyrine and acetaminophen were evaluated in 7 healthy volunteers. On 3 occasions subjects received:1, antipyrine 1.0 g intravenously (i.v.);2, acetaminophen 650 mg i.v.;3, antipyrine 1.0 g and acetaminophen 650 mg i.v. simultaneously.Between Trials 1 and 3, antipyrine elimination t1/2 (17.2 vs 17.4 h), clearance (0.44 vs 0.43 ml·min−1·kg−1) and 24-h recovery of antipyrine and metabolites (313 vs 293 mg) did not differ significantly. Between Trials 2 and 3, acetaminophen Vz was reduced (1.14 vs 1.00 l·kg−1), t1/2 prolonged (2.7 vs 3.3 h), clearance reduced (4.8 vs 3.6 ml·min−1·kg−1), and fractional urinary recovery of acetaminophen glucuronide reduced.Eight additional subjects received 50 mg of lidocaine hydrochloride i.v. in the control state, and on a second occasion immediately after antipyrine 1.0 g given i.v.The two trials did not differ significantly in lidocaine Vz (2.6 vs 2.7 l·kg−1), t1/2 (2.0 vs 2.4 h) or clearance (15.0 vs 13.5 ml·min−1·kg−1).Although acetaminophen does not alter antipyrine kinetics, acute administration of antipyrine appears to impair acetaminophen clearance, possibly via inhibition of glucuronide formation. However, antipyrine has no significant effect on the kinetics of a single i.v. dose of lidocaine.

Contribution of the Gastrointestinal Tract to Lorazepam Conjugation and Clonazepam Nitroreduction

Domestic pigs received single intravenous and oral doses of lorazepam or clonazepam (1 mg/kg), benzodiazepine derivatives biotransformed by glucuronide conjugation and nitroreduction, respectively. Blood samples were simultaneously drawn from portal venous and systemic venous sampling sites during 8 h after dosage. After intravenous dosage with either drug, the area under the serum concentration curve (AUC) for the intact drug, as well as for the principal metabolites (lorazepam glucuronide and 7-aminoclonazepam, respectively), was nearly identical between portal and systemic serum. After oral dosage, absolute systemic availability (relative to intravenous administration) of both lorazepam and clonazepam was incomplete (mean values: 29 and 49%, respectively); however, metabolite levels were also correspondingly lower between oral and intravenous dosages. First-pass hepatic extraction also occurred for both drugs, with mean systemic/portal AUC ratios of 0.60 for lorazepam and 0.74 for clonazepam. Pretreatment with neomycin (1.0 g) had a minimal effect on portal or systemic AUC for intact clonazepam after oral dosage, but 7-aminoclonazepam concentrations were reduced by neomycin pretreatment. Thus incomplete absorption, together with first-pass hepatic biotransformation, appears to explain the incomplete systemic availability of orally administered lorazepam or clonazepam. Biotransformation within the gastrointestinal tract or during absorption through the gastrointestinal mucosa contributes minimally.

Recovery of CYP3A function following single doses of grapefruit juice

Clinical Pharmacology & Therapeutics (2003) 73, P94–P94; doi: