Disposition of [1′-¹⁴C]Stavudine after Oral Administration to Humans

Abstract

ABSTRACT:The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects.

Metabolism and Disposition of [14C]BMS-690514, an ErbB/Vascular Endothelial Growth Factor Receptor Inhibitor, after Oral Administration to Humans

“…The selection of AMS rather than traditional liquid scintillation counting (LSC) was based on a prospective evaluation, which suggested that at a dose of 200 mg and a specific activity of 0.39 Ci/mg, the LSC protocol used in our laboratory (Christopher et al, 2008) would not provide sufficient sensitivity to adequately characterize the elimination phase of the PK profile of radioactivity. In our experience, traditional LSC has not consistently provided adequate sensitivity to fully characterize the PK profile of radioactivity at later time points, particularly in instances in which compounds with low specific activity were administered (Christopher et al, 2008;Zhou et al, 2010). Accelerator mass spectrometry, an ultrasensitive detection technique that relies on measurement of the 14 C/ 12 C ratio, rather than on decay counting (Lappin and Garner, 2004), can help to bridge that gap.…”

Mitochondrial and immunoallergic injury increase risk of positive drug rechallenge after drug-induced liver injury: A systematic review

“…2 Graded liver chemistry elevations were similar in severity in most patients undergoing rechallenge in comparison with the initial liver injury. 2 The mechanisms involved in nucleoside reverse-transcriptase inhibitor-associated hepatotoxicity include the formation of a stavudine epoxide intermediate reactive metabolite 44 and progressive mitochondrial impairment resulting from depletion of mitochondrial DNA. Among nucleoside reverse-transcriptase inhibitors, the rates of hepatotoxicity are highest in those drugs most potently inhibiting mitochondrial DNA synthesis in vitro: zalcitabine-didanosine, stavudine, and zidovudine-lamivudine.…”

Stavudine delivery in an extended release formulation: Will it provide the right in vivo pharmacokinetics - Some key observations

“…[2] The unchanged drug, accounting to approximately 61% of the administered dose, was accounted for in the urine, with a small percentage of radioactivity in the fecal samples, suggesting the predominant role of the renal elimination pathway for its excretion. As urine accounted for almost the entire administered radioactive dose of stavudine, no gastrointestinal absorption issues were cited for this drug.…”

“…As urine accounted for almost the entire administered radioactive dose of stavudine, no gastrointestinal absorption issues were cited for this drug. [2] The half life value of 2.35 hours suggested the need for a second daily dose of stavudine, to maintain the needed plasma / serum threshold concentrations, to elicit its pharmacodynamic response. [2] No data are available in literature pertaining to the likely absorption sites of stavudine after oral administration, although all published pharmacokinetic data, including the 14 C oral dose data, strongly suggest that the absorption of stavudine is likely to happen in the upper gastrointestinal tract itself.…”

“…[2] The half life value of 2.35 hours suggested the need for a second daily dose of stavudine, to maintain the needed plasma / serum threshold concentrations, to elicit its pharmacodynamic response. [2] No data are available in literature pertaining to the likely absorption sites of stavudine after oral administration, although all published pharmacokinetic data, including the 14 C oral dose data, strongly suggest that the absorption of stavudine is likely to happen in the upper gastrointestinal tract itself. [2][3][4] However, there has been a suggestion that stavudine may be subject to carrier-mediated absorption in the preclinical model.…”