Ester prodrugs of morphine improve transdermal drug delivery: a mechanistic study.

Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.

Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats.

A new chronic treatment for inherited disorders of long-chain fatty acid oxidation involves administering up to one-third of dietary calories as triheptanoin, a medium-odd-chain triglyceride (Roe CR, Sweetman L, Roe DS, David F, and Brunengraber H. J Clin Invest 110: 259-269, 2002). Heptanoate and C(5)-ketone bodies derived from its partial oxidation in liver are precursors of anaplerotic propionyl-CoA in peripheral tissues. It was hypothesized that increasing anaplerosis in peripheral tissues would boost energy production. In the present study, we tested the potential of a triheptanoin emulsion as an intravenous nutrient. Normal rats were infused with triheptanoin intravenously or intraduodenally at up to 40% of caloric requirement. The blood concentration ratio (heptanoate/C(5)-ketone bodies) was high with intravenous and low with intraduodenal triheptanoin infusion. During intravenous infusion of triheptanoin, lipolysis was stimulated but appeared compensated by fatty acid reesterification. During intraduodenal infusion of triheptanoin, lipolysis was not stimulated. Our data support the hypothesis that intravenous triheptanoin could be used to treat decompensated patients with long-chain fatty acid oxidation disorders.

Tissue distribution of succinylacetone in the rat in vivo: a possible basis for neurotoxicity in hereditary infantile tyrosinemia.

Neurologic dysfunction is a significant component of hereditary infantile tyrosinemia, an autosomal recessive disorder of man. The specific enzyme defect leads to endogenous production of the biochemical marker compound, succinylacetone (SA). Earlier study of the role which SA plays in generation of the renal Fanconi syndrome, also associated with this disorder, led to speculation that SA might also have neurotoxic effects. Thus, we have studied the distribution and impact on heme metabolism of SA in brain, liver and kidney from rats treated in vivo. Our results show far greater retention of SA in brain and kidney than in liver, by a ratio of approx. 3:1. Delta-aminolevulinate dehydratase (ALAD) was reduced to less than 10% of control activity in all three tissues after three daily injections; after a 7-day recovery, activity was regained at different rates in the three tissues. Total heme content of each tissue showed a steady decline beyond the treatment period, the most marked reduction being found in kidney. Porphyrin intermediates, heme oxygenase activity and cytochrome P-450 content evidenced varying responses to SA exposure which differed from tissue to tissue. Our results show that brain tissue sequesters SA and that heme biosynthesis in brain, as distinct from liver and kidney, is adversely affected. Such effects could result in impaired oxidative metabolism in brain, producing the CNS manifestations of tyrosinemia.

Suppression of graft-versus-host disease by succinyl acetone in a rat allogeneic bone marrow transplantation model.

The efficacy of succinyl acetone (SA, 4,6-dioxoheptanoic acid) was explored in the allogeneic rat bone marrow transplant model of graft-vs.-host disease. Lethally irradiated Wistar Furth rats receiving Fischer 344 allogeneic bone marrow and spleen cells developed severe GVHD, resulting in mortality at 25-45 days posttransplant. Treatment for 14 days with 250 mg/kg/day of SA by Alzet osmotic pumps implanted subcutaneously 3 days before cell transfer prevented GVHD and produced long-term survivors that were allogeneic hematopoietic chimeras. SA doses below 250 mg/kg/day and treatment for less than 14 days were less efficacious. Initiation of SA therapy could be effectively delayed up to 7 days after BMT. Pharmacokinetic studies with i.v. bolus administration in normal CD rats revealed a plasma mean residence time that increased with dose and a systemic clearance that decreased with dose. Three dose-dependent half lives were apparent (ca. 7-18 min, 0.8-3 hr, and 12 hr). The s.c. bioavailability was ca. 82%. Relatively constant plasma SA levels were obtained with s.c. Alzet osmotic pumps, indicating no change in clearance with continuous exposure. Allogeneic BMT exerted no major influence upon SA clearance. These studies show that SA is a robust therapeutic agent that suppressed GVHD in the allogeneic rat BMT model under a variety of circumstances.

Farmacocinética del anticonceptivo inyectable enantato de noretisterona / Pharacokinetics of inyectable contraceptive norethisterone enantate

Se estudió la farmacocinética de una dosis de 200 mg de enantato de noretisterona por vía intramuscular en 11 pacientes, las muestras sanguíneas fueron extraídas durante 15 días y luego semanalmente durante 2 meses. Los níveles de noretisterona en plasma se determinaron por cromatografía líquida de alta presión (HPLC). A partir de las observaciones se determinó el modelo farmacocinético adecuado, este resultó ser el biocompartimental abierto con absorción de primer orden. Obtuvimos los parámetros farmacocinéticos en las diferentes fases y se correlacionaron entre sí. El tiempo de vida media de absorción se correlacionó positivamente con el tiempo de vida media de distribución, con el tiempo en que se alcanza la concentración máxima, y con índice de masa corporal. El volumen de distribución se correlacionó positivamente con el tiempo de vida media de eliminación y con el aclaramiento plasmático

Farmacocinética del anticonceptivo inyectable enantato de noretisterona / Pharmacokinetics of inyectable contraceptive norethisterone enantate

Se estudió la farmacocinética de una dosis de 200 mg de enantato de noretisterona por vía intramuscular en 11 pacientes, las muestras sanguíneas fueron extraídas durante 15 días y luego semanalmente durante 2 meses. Los níveles de noretisterona en plasma se determinaron por cromatografía líquida de alta presión (HPLC). A partir de las observaciones se determinó el modelo farmacocinético adecuado, este resultó ser el biocompartimental abierto con absorción de primer orden. Obtuvimos los parámetros farmacocinéticos en las diferentes fases y se correlacionaron entre sí. El tiempo de vida media de absorción se correlacionó positivamente con el tiempo de vida media de distribución, con el tiempo en que se alcanza la concentración máxima, y con índice de masa corporal. El volumen de distribución se correlacionó positivamente con el tiempo de vida media de eliminación y con el aclaramiento plasmático