Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.
We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (¼ of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers.
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA. ghb2@musc.edu
Guinevere H
GH
Bell
Andrew J
AJ
Novak
William C
WC
Griffin
Kennerly S
KS
Patrick
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D004951:Esterification; D000431:Ethanol / Q000008:administration & dosage*; D008401:Gas Chromatography-Mass Spectrometry; D007408:Intestinal Absorption / Q000187:drug effects; D007536:Isomerism; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D012869:Skin Absorption / Q000187:drug effects; D057968:Transdermal Patch
D000697:Central Nervous System Stimulants; D008774:Methylphenidate; D000431:Ethanol; C042400:ethylphenidate
Behav Pharmacol. 2011 Feb;22(1):14-22
21160424
Drug Metab Dispos. 2000 Jun;28(6):620-4
10820132
Biomed Chromatogr. 2004 Jan;18(1):45-50
14872548
Drug Metab Dispos. 2009 Sep;37(9):1819-25
19487248
Am J Hum Genet. 2008 Jun;82(6):1241-8
18485328
Pharmacol Biochem Behav. 2010 May;95(3):267-72
20122954
Pharm Res. 2000 Apr;17(4):381-4
10870979
Paediatr Drugs. 2010 Jun;12(3):165-75
20481646
Life Sci. 1997;61(19):1879-87
9364192
Drug Metab Pharmacokinet. 2004 Oct;19(5):352-62
15548846
J Med Chem. 2005 Apr 21;48(8):2876-81
15828826
Arzneimittelforschung. 2010;60(5):238-44
20533759
J Can Acad Child Adolesc Psychiatry. 2008 Nov;17(4):181-2
19018319
J Am Acad Child Adolesc Psychiatry. 1991 Sep;30(5):773-5
1938793
J Learn Disabil. 1998 Nov-Dec;31(6):533-44
9813951
Am J Psychiatry. 2003 Nov;160(11):1909-18
14594733
J Pharmacol Exp Ther. 1970 May;173(1):158-65
4392603
Pharm Res. 1993 Jan;10(1):14-21
8430051
Drugs Today (Barc). 2007 Aug;43(8):515-27
17925883
Drug Metab Dispos. 2009 Feb;37(2):264-7
19022936
J Toxicol Clin Toxicol. 2000;38(6):625-30
11185969
Clin Pharmacol Ther. 2007 Mar;81(3):346-53
17339864
Pharmacotherapy. 2003 Oct;23(10):1281-99
14594346
J Clin Pharmacol. 2000 Oct;40(10):1141-9
11028253
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Feb 1;862(1-2):140-9
18155648
Biol Psychiatry. 2005 Jun 1;57(11):1442-51
15950019
Arch Pediatr Adolesc Med. 2000 Dec;154(12):1199-203
11115302
Drug Metab Dispos. 1982 Nov-Dec;10(6):708-9
6130929
J Clin Psychopharmacol. 1999 Aug;19(4):362-6
10440465
J Psychoactive Drugs. 2006 Mar;38(1):43-56
16681175
J Pharm Sci. 2002 Dec;91(12):2571-8
12434400
Drug Alcohol Depend. 2006 Sep 15;84(2):135-43
16480836
Biomed Chromatogr. 2004 Jun;18(5):275-81
15236434
N Engl J Med. 2006 Jun 22;354(25):2637-41
16790695
Biol Chem. 1996 Oct;377(10):647-51
8922593
Environ Mol Mutagen. 2008 Oct;49(8):585-93
18618596
J Atten Disord. 2005 Nov;9(2):384-91
16371661
Behav Pharmacol. 2007 Feb;18(1):39-51
17218796
J Pharm Sci. 1997 Dec;86(12):1494-6
9423167
Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):661-5
19442029
J Am Acad Child Adolesc Psychiatry. 2004 Nov;43(11):1406-14
15502600
Hum Psychopharmacol. 2007 Dec;22(8):529-36
17910020
N Engl J Med. 2005 Jan 13;352(2):165-73
15647579
J Pharmacol Exp Ther. 1982 Oct;223(1):45-9
7120126
J Clin Psychopharmacol. 2002 Dec;22(6):633-4
12454570
Clin Toxicol (Phila). 2007 Oct-Nov;45(7):737-52
18058301
Pediatrics. 1983 Jul;72(1):56-9
6866592
J Am Acad Child Adolesc Psychiatry. 2003 Mar;42(3):288-94
12595781
Drug Metab Dispos. 1981 Sep-Oct;9(5):415-23
6117439
AAPS PharmSciTech. 2010 Sep;11(3):1054-7
20582494
J Pharmacol Exp Ther. 1987 Apr;241(1):152-8
3572779
Forensic Sci Int. 2010 Mar 20;196(1-3):59-63
20096514
Drug Metab Rev. 2007;39(4):659-98
18058329
J Am Acad Child Adolesc Psychiatry. 2008 Jan;47(1):21-31
18174822
J Pharmacol Exp Ther. 2004 Aug;310(2):469-76
15082749
Toxicology. 2010 Apr 11;270(2-3):59-65
20097249
Hum Psychopharmacol. 2009 Jan;24(1):1-17
19051222
Prim Care Companion J Clin Psychiatry. 2000 Oct;2(5):159-164
15014637
Recent Dev Alcohol. 1998;14:437-55
9751958
Neuropharmacology. 2009 Dec;57(7-8):687-93
19631228
Pharmacotherapy. 2009 Jun;29(6):656-79
19476419
Mini Rev Med Chem. 2001 May;1(1):101-11
12369995
J Atten Disord. 2002;6 Suppl 1:S101-7
12685524
J Pharmacol Exp Ther. 1984 Oct;231(1):61-5
6491975
J Med Chem. 1981 Oct;24(10):1237-40
7328584
Psychopharmacology (Berl). 1996 Jan;123(1):26-33
8741951
Pharmacotherapy. 2003 May;23(5):609-17
12741435
J Psychopharmacol. 2010 Jun;24(6):897-904
19282420
Genet Test Mol Biomarkers. 2010 Dec;14(6):749-51
20858053
J Clin Psychiatry. 2000 Apr;61(4):244-51
10830144
Drug Metab Dispos. 2009 Feb;37(2):247-53
19005027
J Pharm Sci. 1991 Jul;80(7):707-8
1941573
Int J Pharm. 2002 Apr 2;236(1-2):35-42
11891068
J Adolesc Health. 2004 Dec;35(6):501-4
15581530
Am J Psychiatry. 2006 Mar;163(3):387-95
16513858
Psychopharmacol Bull. 2008;41(1):19-33
18362868
Subst Abuse Treat Prev Policy. 2007 Oct 31;2:32
17974020
Addict Behav. 2005 Aug;30(7):1342-50
16022931
Am J Psychiatry. 1993 Dec;150(12):1792-8
8238632
J Atten Disord. 2010 Jul;14(1):57-68
19794135
J Child Adolesc Psychopharmacol. 2008 Aug;18(4):355-64
18759645
J Psychopharmacol. 2009 Mar;23(2):194-205
18515459
J Pharmacol Exp Ther. 2006 Dec;319(3):1467-76
16943252
Addiction. 2005 Jan;100(1):96-106
15598197