Synthesis and <i>in Vitro</i> Degradation of Testosterone‐Lipid Conjugates

Scriba, Gerhard K. E.

doi:10.1002/ardp.19953280313

Cited by 14 publications

(12 citation statements)

References 15 publications

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“…TTC (Figure 1) was synthesized by the N,N‐dicyclohexylcarbodimide‐mediated esterification of 2‐(1,3‐dipalmitoylglyceryl)succinic acid mono ester with testosterone (Scriba, 1995a). Purity was assessed by high‐performance liquid chromatography and found to be greater than 99%.…”

Section: Methodsmentioning

confidence: 99%

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Oral Testosterone‐Triglyceride Conjugate in Rabbits: Single‐Dose Pharmacokinetics and Comparison With Oral Testosterone Undecanoate

Amory

Scriba²,

Amory

et al. 2003

Journal of Andrology

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Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 Ϯ 7.9 nmol/L vs TU: 11.9 Ϯ 2.1 nmol/L; P Ͻ .001) and 4 mg/kg (TTC: 11.5 Ϯ 4.2 nmol/L vs TU: 3.6 Ϯ 1.0 nmol/L; P Ͻ .001). In addition, the AUC was 1.8 to 2.6 times greater for TTC than TU at both doses (P Ͻ .05). The terminal half-life for both TU and TTC was between 3 and 5 hours and was not significantly different. We conclude that oral TTC is rapidly absorbed from the rabbit intestine and results in elevated concentrations of serum testosterone. The absorption of TTC appears to be superior to that of TU; however, the in vivo persistence of the 2 compounds is similar. TTC may offer an alternative to the use of TU for oral testosterone therapy. Further testing of this compound is warranted.

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Section: Methodsmentioning

confidence: 99%

“…One of us (G.K.E.S.) has synthesized such a compound and reported on its in vitro characteristics (Scriba, 1995a). Moreover, this type of drug‐triglyceride conjugate has been demonstrated to improve the oral delivery of other poorly water‐soluble drugs, such as phenytoin (Scriba et al, 1995b).…”

mentioning

confidence: 99%

Oral Testosterone‐Triglyceride Conjugate in Rabbits: Single‐Dose Pharmacokinetics and Comparison With Oral Testosterone Undecanoate

Amory

Scriba²,

Amory

et al. 2003

Journal of Andrology

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“…The twin challenges of GI stability and systemic lability may be met using a combination of βMe‐branched linkers and SI groups to stabilize against GI hydrolysis and promote systemic drug release, respectively. This marks a considerable advance over previous approaches that rely on direct conjugation or simple alkyl spacers, where GI stability is reduced and drug release is limited . The technology is adaptable to different SI groups and the conjugation chemistries may be adjusted for application to drugs with hydroxyl, amine, thiol, or carboxylic acid functionality.…”

Section: Figurementioning

confidence: 99%

Glyceride‐Mimetic Prodrugs Incorporating Self‐Immolative Spacers Promote Lymphatic Transport, Avoid First‐Pass Metabolism, and Enhance Oral Bioavailability

Quach

Han

et al. 2016

Angew Chem Int Ed

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First‐pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first‐pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first‐pass drug, glyceride‐mimetic prodrugs incorporating self‐immolative (SI) spacers, resulted in remarkable increases (up to 90‐fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first‐pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.

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“…For related literature, see: Osanai et al (1997); Scriba (1993Scriba ( , 1995. The structure of a related derivative is reported in the preceeding paper, see: Kuś et al (2009).…”

Section: Related Literaturementioning

confidence: 99%

“…Non-symmetrical esters of succinic acid have been used for the synthesis of prodrugs that release the corresponding drugs very slowly; e.g. steroid drugs (Scriba, 1995) or Phenytoin (Scriba, 1993). Solketal (D,L-isopropylideneglycerol, Aldrich) was used for the synthesis of compound 1.…”

Section: S1 Commentmentioning

confidence: 99%