Local Toxicity of Different Drugs after Intramuscular or Intralipomatous Injection in Pigs: Serum Concentrations after Three Different Formulations of cis(Z)–Clopenthixol

Abstract

Findings made by computerized tomography scanning of pelvis of patients suggested that the majority of injections intended to be intramuscular in fact are delivered in the fat tissue. This finding has raised the question what difference it makes when drugs are injected intramuscularly or intralipomatously. We have studied local toxicity after intramuscular or intralipomatous injection of different drugs in pigs, which have a subcutaneous layer of fat comparable to that of man. The pigs were killed 1, 3, 7 or 14 days after injection of antibiotics, vitamins, neuroleptics, diazepam, digoxin, pentazocine, sulphadimidine and vehicles. The tissues at the injection site were examined macro- and microscopically. In another series of experiments an aqueous or two different oily preparations of the neuroleptic drug cis(Z)-clopenthixol were given intramuscularly or intralipomatously to pigs and a series of blood samples were taken for drug level determination. The tissue examinations showed that all drugs causing local muscle damage after intramuscular injection caused considerably less extensive damage with a faster regeneration after intralipomatous injection. The pharmacokinetic study showed that there was virtually no difference between plasma-concentration-time curves after intramuscular or intralipomatous injection. Our findings indicate that intralipomatous injection of irritating drugs is better tolerated than intramuscular injection since intralipomatous injection causes less local toxicity. Our findings also suggest that the pharmacokinetics are not different. However, further studies are required to substantiate whether the findings are of general relevance.

Prolonged Release from the Injection Site of Morphine from Morphine Esters in an Oil Vehicle Given by Intramuscular Injection to Pigs

“…The trend seen in this study, sustained release from the oil vehicle with increasing chain length of the ester, has also been seen for esters of neuroleptic drugs (Dreyfuss et al 1976;Svendsen & Jerrgensen 1980;Svendsen et al 1985;Aaes-Jsrgensen 1989). When comparing the depot effect achieved, there is, however, a clear difference between the two groups of drugs.…”

“…The pig model was chosen since previous studies have shown that pigs produce Author for correspondence: Aksel Jergensen, Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark (fax +45 44 94 30 40). blood concentration-time profiles of oil formulations with the same general features as those produced by man (Svendsen et al 1985; Aaes-Jerrgensen 1989).…”

“…The pig model was chosen since previous studies have shown that pigs produce Author for correspondence: Aksel Jergensen, Leo Pharmaceutical Products, Industriparken 55, DK-2750 Ballerup, Denmark (fax +45 44 94 30 40). blood concentration-time profiles of oil formulations with the same general features as those produced by man (Svendsen et al 1985; Aaes-Jerrgensen 1989).The enzymatic cleavage of M3P and M3H to give morphine has been studied in human plasma in vitro and halflives shorter than one minute were found (Drustrup et al 1991). It is reasonable therefore to assume that the cleavage of the three esters in muscle proceeds with a high rate.Six Danish domestic pigs, weighing 29-37 kg, were used for the study.…”

Factors influencing time course of pain after depot oil intramuscular injection of testosterone undecanoate

“…On the other hand, the local inflammatory reaction to pressure and/or necrosis around the injection site does not appear much different between the skeletal muscle and fat [19]. Although the volume and site of injection significantly influence pharmacokinetics of injectable androgen ester in oil vehicle in men [43], limited nonhuman experimental data suggests that the pharmacokinetics of drug delivery into the bloodstream from injectable oil vehicle depots may not differ substantially between injections into subdermal fat or muscle [20]. At extremes, such injury and/or inflammatory effects may also cause rare side effects such as sciatic nerve injury following gluteal IM injections [44].…”

“…Experimental animal studies show that oil-based injections produce local necrosis of muscle, leading to increases in circulating creatinine kinase levels [17][18][19]. Localized tissue damage at the injection site accounts for the pain, redness and sterile inflammation, mostly low grade and readily tolerated, following IM administration of oil vehicle injections [20]. The irritation and inflammatory reactions arise from the intrinsic physicochemical properties of either the drugs, excipients [21] or vehicle [22,23].…”