PMID- 1447905
OWN - NLM
STAT- MEDLINE
DCOM- 19921229
LR  - 20170214
IS  - 0023-6772 (Print)
IS  - 0023-6772 (Linking)
VI  - 26
IP  - 4
DP  - 1992 Oct
TI  - Subcutaneous administration of HMG-CoA reductase inhibitors in hyperlipidaemic 
      and normal rats.
PG  - 269-80
AB  - Recent reports demonstrate a hypocholesterolaemic effect of daily subcutaneous 
      injections of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase 
      inhibitors in different rat models of hyperlipidaemia. However, this effect is 
      not seen after oral administration of HMG-CoA reductase inhibitors in rats. We 
      found that oral administration of the HMG-CoA reductase inhibitor Simvastatin 
      also had no effect on plasma cholesterol in severely hyperlipidaemic Nagase 
      analbuminaemic rats (NAR). Simvastatin (an apolar compound dissolved in propylene 
      glycol) was infused continuously for 28 days into the subcutis of control 
      Sprague-Dawley rats (SDR) and NAR using an implanted osmotic pump. All doses 
      which were effective in reducing cholesterol in the NAR (reductions up to 
      approximately 60%), reduced apolipoprotein AI but not apolipoprotein B and caused 
      a severe inflammatory reaction in the dermis. Similar toxicity was observed in 
      the SDR. Subcutaneous administration of the vehicle (propylene glycol) did not 
      cause this reaction and did not affect plasma lipids. Administration of 
      Lovastatin in osmotic pumps resulted in a similar inflammatory reaction. 
      Incorporation of Simvastatin into liposomes did not diminish the toxic effect. On 
      the other hand, infusion of Pravastatin (a polar HMG-CoA reductase inhibitor 
      dissolved in isotonic saline) caused no changes in the dermis and had no effect 
      on plasma lipids in NAR or SDR. Liver microsomes prepared from the 
      Pravastatin-treated rats demonstrated a 3- to 4-fold increase in HMG-CoA 
      reductase activity as compared to untreated rats, confirming uptake of the drug. 
      We conclude that continuous subcutaneous administration of the HMG-CoA reductase 
      inhibitors Simvastatin, Lovastatin and Pravastatin for 28 days may not reduce 
      plasma cholesterol in rats by a mechanism which is related to inhibition of 
      HMG-CoA reductase activity in the liver. The decrease of plasma cholesterol 
      effected by subcutaneous infusion of Simvastatin or Lovastatin in NAR coincides 
      with, and may be related to inflammatory changes caused by administering these 
      compounds into the dermis.
FAU - Joles, J
AU  - Joles J
AD  - Department of Nephrology, Medical Faculty, University of Utrecht, The 
      Netherlands.
FAU - Willekes-Koolschijn, N
AU  - Willekes-Koolschijn N
FAU - Koomans, H
AU  - Koomans H
FAU - Van Tol, A
AU  - Van Tol A
FAU - Geelhoed-Mieras, T
AU  - Geelhoed-Mieras T
FAU - Crommelin, D
AU  - Crommelin D
FAU - Van Bloois, L
AU  - Van Bloois L
FAU - Krajnc-Franken, M
AU  - Krajnc-Franken M
FAU - Cohen, L
AU  - Cohen L
FAU - Griffioen, M
AU  - Griffioen M
AU  - et al.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Lab Anim
JT  - Laboratory animals
JID - 0112725
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 9LHU78OQFD (Lovastatin)
RN  - AGG2FN16EV (Simvastatin)
RN  - KXO2KT9N0G (Pravastatin)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Anticholesteremic Agents/*administration & dosage/toxicity
MH  - Female
MH  - *Hydroxymethylglutaryl-CoA Reductase Inhibitors
MH  - Hypercholesterolemia/blood/drug therapy/pathology
MH  - Infusion Pumps, Implantable
MH  - Injections, Subcutaneous
MH  - Lovastatin/*administration & dosage/*analogs & derivatives/toxicity
MH  - Pravastatin/*administration & dosage/toxicity
MH  - Rats
MH  - Rats, Mutant Strains
MH  - Rats, Sprague-Dawley
MH  - Simvastatin
EDAT- 1992/10/01 00:00
MHDA- 1992/10/01 00:01
CRDT- 1992/10/01 00:00
PHST- 1992/10/01 00:00 [pubmed]
PHST- 1992/10/01 00:01 [medline]
PHST- 1992/10/01 00:00 [entrez]
AID - 10.1258/002367792780745689 [doi]
PST - ppublish
SO  - Lab Anim. 1992 Oct;26(4):269-80. doi: 10.1258/002367792780745689.