E. Thomas Everhart

Bioavailability of Sublingual Buprenorphine

Buprenorphine administered sublingually is a promising treatment for opiate dependence. Utilizing a new, sensitive, and specific gas chromatographic electron‐capture detector assay, the absolute bioavailability of sublingual buprenorphine was determined in six healthy volunteers by comparing plasma concentrations after 3‐ and 5‐minute exposures to 2 mg sublingual and 1 mg intravenous buprenorphine. The amount of unabsorbed buprenorphine in saliva was measured after 2‐, 4‐, and 10‐minute exposures to 2 mg sublingual buprenorphine in 12 participants. Pharmacokinetic parameters were analyzed by analysis of variance; bioequivalence was evaluated by the Schuirmann two‐sided test. The 3‐ and 5‐ minute sublingual exposures each allowed 29 ± 10% bioavailability (area under the plasma concentration—time curve unextrapolated) and were bioequivalent. Buprenorphine recovered from saliva after 2‐, 4‐, and 10‐minute exposures was, on average, 52% to 55% of dose. Increased saliva pH was correlated with decreased recovery from saliva. Study results indicate that bioavailability of sublingual buprenorphine is approximately 30%. Sublingual exposure times between 3 and 5 minutes produce equivalent results. Buprenorphine remaining in saliva causes an almost twofold overestimation of bioavailability.

Buprenorphine Pharmacokinetics: Relative Bioavailability of Sublingual Tablet and Liquid Formulations

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM‐III‐R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration‐time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.

The pharmacology of cocaethylene in humans following cocaine and ethanol administration

BACKGROUND Concurrent use of cocaine and alcohol results in formation of a cocaine homolog and metabolite-cocaethylene. METHODS To characterize cocaethylene pharmacology, ten paid volunteer subjects were given deuterium-labeled (d(5)) cocaine (0.3, 0.6, and 1.2 mg/kg and cocaine placebo) by a 15-min constant rate intravenous injection 1 h after a single oral dose of ethanol (1 g/kg) or ethanol and cocaine placebo using a double-blind, crossover design. Six of the same volunteers subsequently received a 1.2 mg/kg dose of cocaine alone. A small (7.5 mg) nonpharmacologically active dose of deuterium-labeled cocaethylene-d(3) was concurrently administered with the cocaine to enable calculation of absolute cocaethylene formation and clearance. Plasma and urine cocaine, cocaethylene, and benzoylecgonine concentrations, physiologic and subjective effects were measured. RESULTS When co-administered with ethanol, 17+/-6% (mean+/-S.D.) of the cocaine was converted to cocaethylene. Cocaethylene peak plasma concentrations and AUC increased proportionally to the cocaine dose. Ethanol ingestion prior to cocaine administration decreased urine benzoylecgonine levels by 48% and increased urinary cocaethylene and ecgonine ethyl ester levels. Subjects liked and experienced more total intoxication after the combination of cocaine and ethanol than after either drug alone. CONCLUSIONS In the presence of ethanol, the altered biotransformation of cocaine resulted in 17% of an intravenous cocaine dose being converted to cocaethylene and relatively lower urinary concentrations of benzoylecgonine.

Human pharmacology of the methamphetamine stereoisomers.

To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers.

The Bioavailability of Intranasal and Smoked Methamphetamine

Patients in harm‐reduction treatment programs are switching from intravenous to otherroutes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally.

Characterization of cannabidiol-mediated cytochrome P450 inactivation

Cannibidiol (CBD) has been shown to impair hepatic drug metabolism in several animal species and to markedly inhibit mouse hepatic microsomal delta 1-tetrahydrocannabinol (THC) metabolism by inactivating specific cytochrome P450s (P450) belonging to the 2C and 3A subfamilies. Elucidation of the mechanism of CBD-mediated P450 inhibition would be clinically very important for predicting its effect on metabolism of THC and the many other clinically important drugs known to be metabolized by P450s 2C and 3A. CBD-mediated inactivation of mouse hepatic microsomal P450s did not decrease hepatic microsomal heme content. However, [14C]CBD was found covalently bound to microsomal protein in an approximately equimolar ratio to P450 loss. Immunoprecipitation of microsomal protein with antibodies raised against either P450 2C or 3A revealed that approximately equal amounts of [14C]-CBD were bound to each of these P450s after CBD-mediated inactivation. Furthermore, this specific P450 binding was equivalent to P450 loss and accounted for nearly all of the microsomal [14C]CBD irreversible binding. Although > 80% of the enzyme activities attributed to P450s 2C and 3A were inactivated by CBD at the anticonvulsant dose of 120 mg/kg, P450 2C was approximately 3-fold more sensitive than P450 3A at the lower CBD doses tested. CBD analogs were synthesized in order to elucidate the chemical pathways for CBD-mediated P450 inactivation in vivo. Oxidations at allylic carbon positions or saturation of either the exocyclic double bond or both double bonds of the terpene moiety did not markedly affect the inhibitory properties of the analogs. Methylation of both phenolic groups of the resorcinol moiety completely blocked the P450-inhibitory properties of this analog, revealing the involvement of a free hydroxyl group in the inactivation process. Rotation of the resorcinol moiety in abnormal-CBD did not impair the inhibitory properties of the analog, suggesting that the position of the hydroxyl group relative to the terpene ring is unimportant. Further studies are required to fully understand the chemical basis of CBD-mediated P450 inactivation.

Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol

Cannabidiol (CBD) has been shown to be a selective inactivator of cytochromes P450 (P450s) 2C and 3A in the mouse and, like many P450 inactivators, it can also induce P450s after repeated administration. The inductive effects of CBD on mouse hepatic P450s 2B, 3A, and 2C were determined using cDNA probes, polyclonal antibodies, and specific functional markers. P450 2B10 mRNA was increased markedly after repeated CBD administration and correlated well with increased P450 2B immunoquantified content and functional activity. On the other hand, although the 2-fold increase in P450 3A mRNA detected after repeated CBD administration was consistent with the increased immunoquantified P450 3A protein content, the lack of an observable increase in P450 3A-specific functional activity suggested subsequent inactivation of the induced P450 3A. Repeated CBD treatment increased P450 2C mRNA content 2-fold, but did not increase either the P450 2C immunoquantified content or its functional activity. The effect of CBD treatment on the ability of tetrahydrocannabinol (THC) to induce P450 2B was also determined. A THC dose that did not induce P450 2B significantly was administered alone or in combination with a CBD dose that markedly inactivated P450s 2C- and 3A but submaximally increased P450 2B functional activity. The combination of THC and CBD did not increase P450 2B-catalyzed activity significantly over that observed after CBD treatment alone. Thus, prior CBD-mediated P450 inactivation does not appear to increase the ability of THC to induce P450 2B. To further characterize the relationship between P450 inactivation and induction, several structurally diverse CBD analogs with varying P450 inactivating potentials were tested for their ability to induce P450 2B. At least one CBD analog that is an effective P450 inactivator failed to induce P450 2B, while at least one CBD analog that is incapable of inactivating P450 was found to be a very good P450 2B inducer. It therefore appears that inherent structural features of the CBD molecule rather than its ability to inactivate P450 determine P450 2B inducibility. The complex effects of CBD treatment on P450 inactivation and induction have the potential to influence the pharmacological action of many clinically important drugs known to be metabolized by these various P450s. The mechanism of CBD-mediated P450 induction remains to be elucidated but does not appear to be related to CBD-mediated P450 inactivation.

The synthesis of deuterium‐labelled cocaine, cocaethylene and metabolites

We describe the syntheses of benzoylecgonine (1,1,1- 2 H 3 )methyl ester [( 2 H 3 ) cocaine], ( 2 H 5 )benzoylecgonine, ( 2 H 5 )benzoylecgonine methyl ester [( 2 H 5 )cocaine], benzoylecgonine (2,2,2- 2 H 3 )ethyl ester [( 2 H 3 )cocaethylene], ( 2 H 5 )benzoylecgonine ethyl ester [( 2 H 5 )cocaethylene], ( 2 H 5 )benzoylecgonine (2,2,2- 2 H 3 )ethyl ester [( 2 H 8 )cocaethylene], ecgonine (1,1,1- 2 H 3 )methyl ester, ecgonine (2,2,2- 2 H 3 )ethyl ester, ecgonine (1,1,2,2,2- 2 H 5 )ethyl ester and anhydroecgonine (1,1,1- 2 H 3 )methyl ester. ( 2 H 5 )Cocaine and ( 2 H 3 )cocaethylene have been administered to human subjects to study the interactions of cocaine and ethanol. The other eight compounds were utilized as analytical standards or internal standards for GC-MS quantitation of cocaine and its metabolites in biological fluids.

The mass balance of buprenorphine in humans

Clinical Pharmacology & Therapeutics (1999) 65, 152–152; doi:

A Convenient Procedure for Isolation of Alcohols After Cleavage of Protective Groups with Tetra-n-Butylammonium Fluoride

Abstract Polar alcohols obtained from their β-(trimethylsilyl) ethoxymethyl (SEM) ethers by deprotection using the tetra-n-butylammonium fluoride reagent, can be efficiently isolated after quantitative removal of the excess reagent as the insoluble tetra-n-butylammonium perchlorate salt. Standard extractive workup then gives the alcohols in high yield. The method is applicable to any reaction involving the use of tetra-n-butylammonium fluoride for the removal of protective groups.