No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects.

Maraviroc is a C-C chemokine receptor type-5 antagonist approved for the treatment of HIV-1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism.

Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5.

Maraviroc (MVC) is a CCR5 coreceptor antagonist indicated in combination with other antiretroviral agents for the treatment of CCR5-tropic human immunodefinciency virus-1 infection. In this study, the metabolism of MVC was investigated in human liver microsomes to delineate the relative roles of CYP3A4 and CYP3A5. MVC is metabolized to five hydroxylated metabolites, all of which were biosynthesized and identified using mass and NMR spectroscopy.

Two-year carcinogenicity study in rats with a nonnucleoside reverse transcriptase inhibitor.

Administration of lersivirine, a nonnucleotide reverse transcriptase inhibitor, daily by oral gavage to Sprague-Dawley rats for up to 2 yr was associated with decreased survival, decreased body weights, and an increase in neoplasms and related proliferative lesions in the liver, thyroid, kidney, and urinary bladder. Thyroid follicular adenoma and carcinoma, the associated thyroid follicular hypertrophy/hyperplasia, hepatocellular adenoma/adenocarcinoma, altered cell foci, and hepatocellular hypertrophy were consistent with lersivirine-related induction of hepatic microsomal enzymes. Renal tubular adenoma and renal tubular hyperplasia were attributed to the lersivirine-related exacerbation of chronic progressive nephropathy (CPN), while urinary bladder hyperplasia and transitional cell carcinoma in the renal pelvis and urinary bladder were attributed to urinary calculi.

Metabolism-guided design of short-acting calcium-sensing receptor antagonists.

As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.

Multiple species metabolism of PHA-568487, a selective alpha 7 nicotinic acetylcholine receptor agonist.

The quinuclidine PHA-0568487(1) is an agonist of the alpha 7 nicotinic acetylcholine receptor that was designed to mitigate the bioactivation associated with the core scaffold and subsequently remove associated liabilities with in vivo tolerability. The drug metabolites of 1 in nonclinical species were identified in plasma and urine of rats, dogs and monkeys receiving oral administrations of 1. The in vitro biotransformation of 1 was subsequently investigated in multiple species employing cryopreserved hepatocytes, hepatic subcellular fractions and recombinantly-expressed human P450 enzymes.

Toxicophores, reactive metabolites and drug safety: when is it a cause for concern?

It is generally accepted that bioactivation of relatively inert functional groups (toxicophores) to reactive metabolites is an obligatory step in the pathogenesis of certain idiosyncratic adverse drug reactions (IADRs). IADRs cannot be detected in regulatory animal toxicity studies and, given their low frequency of occurrence in humans (1 in 10,000 to 1 in 100,000), they are often not detected until the drug has gained broad exposure in a large patient population. The detection of IADRs during late clinical trials or after a drug has been released can lead to an unanticipated restriction in its use, and even in its withdrawal.

Hydrolysis of a series of parabens by skin microsomes and cytosol from human and minipigs and in whole skin in short-term culture.

Parabens are esters of 4-hydroxybenzoic acid and used as anti-microbial agents in a wide variety of toiletries, cosmetics and pharmaceuticals. It is of interest to understand the dermal absorption and hydrolysis of parabens, and to evaluate their disposition after dermal exposure and their potential to illicit localised toxicity. The use of minipig as a surrogate model for human dermal metabolism and toxicity studies, justifies the comparison of paraben metabolism in human and minipig skin.

The distribution of esterases in the skin of the minipig.

Skin esterases serve an important pharmacological function as they can be utilised for activation of topically applied ester prodrugs. Understanding the nature of these enzymes, with respect to their role and local activity, is essential to defining the efficacy of ester prodrugs. Minipigs are used as models to study the kinetics of absorption of topically applied drugs.

Specificity of procaine and ester hydrolysis by human, minipig, and rat skin and liver.

The capacity of human, minipig, and rat skin and liver subcellular fractions to hydrolyze the anesthetic ester procaine was compared with carboxylesterase substrates 4-methylumbelliferyl-acetate, phenylvalerate, and para-nitrophenylacetate and the arylesterase substrate phenylacetate. Rates of procaine hydrolysis by minipig and human skin microsomal and cytosolic fractions were similar, with rat displaying higher activity. Loperamide inhibited procaine hydrolysis by human skin, suggesting involvement of human carboxylesterase hCE2.

Using a tritiated compound to elucidate its preclinical metabolic and excretory pathways in vivo: exploring tritium exchange risk.

The metabolism and excretion of N-(3R)-1-azabicyclo[2.2.2]oct-3-ylfuro[2,3-c]pyridine-5-carboxamide (1), an agonist of the alpha7 nicotinic acetylcholinergic receptor, were determined in both Sprague-Dawley rats and beagle dogs using [3H]1.

Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats.

Our study objectives were: To quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study. To quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations. To conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds.